Alkaptonuria

Figures & data

Figure 1. Adapted from reference 3. The diagram illustrates the normal phenylalanine and tyrosine degradation pathway, enzymes involved and defects that can occur (highlighted blue). The metabolism of HGA occurs in the liver, and HGD is an enzyme expressed in this organ.

Figure 2. Taken from reference 11. The map illustrates the current number of AKU patients identified worldwide.

Table 1. Summarizes the location of HGA pigment deposition through all layers of an articulating joint.

Tissue	Areas of pigmentation
Bone	Intracellular
Cartilage	Intra- and extra-cellular
Synovium	Extracellular
Capsule	Intra- and extra-cellular
Ligament	Extra-cellular
Tendon	Intra- and extra-cellular

Bone has predominantly intracellular pigmentation, located in both osteocytes and osteoclasts. Mineralized bone matrix is resistant to pigmentation, it is thought that the mineral crystals located on bone collagen are protective against HGA and its subsequent binding and polymerization on the collagen fibers. The chondrocytes within cartilage show numerous intracellular deposits. Pigment deposition within the synovium appears to be caused by large fragments of ochronotic cartilage that have broken off from the articular surface and have embedded in the synovium.²⁸ Although ligaments show large extracellular deposits, little work has looked at the cellular components of ligaments. Investigation into tendons has demonstrated both intra- and extra-cellular pigmentation.²⁵

Table 2. Adapted from reference 21 The table shows the differences between peripheral ochronotic arthropathy and osteoarthritis.³¹

Peripheral Ochronotic Arthropathy vs. Osteoarthritis
	Joint Involved	Narrowing of Joint Space	Osteophytosis
Ochronosis	Knees, shoulders +++ Hips, elbows and ankles ++ Sacroiliac Joints ±	Symmetric or asymmetric	Observed macroscopically not detectable radiographically
Osteoarthritis	Hips +++ Knees +++ Hands +++	Symmetric or asymmetric	Present

+++, significant involvement; ++, some involvement; ±, little or no involvement

Table 3. Adapted from reference 21. The table shows the radiographic differences between ankylosing spondylitis and ochronotic spondylarthropathy.

Ochronotic spondylarthropathy vs. ankylosing spondylitis (radiographic features)
	Ochronosis	Ankylosing spondylitis
Calcification of intervertebral discs	++	±
Syndesmophytes	±	+++
Ossification of ligaments	+++	+
Erosion and fusion of sacroiliac joints	±	+++
Osteoporotic vertebral bodies	++	+

+++, significant involvement; ++, some involvement; +, minimal involvement; ±, little or no involvement

Table 4. Adapted from reference 44. Information on current and future therapies available from references 5 and 46.

Treatment	Summary
Ascorbic acid	Efficacy unproven, increases HGA production, may exacerbate condition
Low protein diet	Efficacy in adults unproven, compliance difficult
Lifestyle counselling	Underused, lack of evidence base
Physiotherapy	Underused
Pain control	Widely used, incompletely effective
Organ replacement	Unjustified for a condition with preserved lifespan
Palliative surgery	Effective but invasive
Liver transplant	Not frequently used, lack of evidence base
Reverse pigment binding	Not yet available
HGA lowering therapy:
Nitisinone	Not shown to alter outcomes, increases tyrosine
Enzyme replacement	Not yet available
Gene replacement	Not yet available

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