Acute anterior uveitis as the initial presentation of alkaptonuria
SS John1, P Padhan2, JV Mathews2, S David1,
1 Department of Ophthalmology, Christian Medical College, Vellore, India
2 Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore, India
S S John
Department of Ophthalmology, Christian Medical College, Vellore
Alkaptonuria is a rare autosomal recessive metabolic disorder that may present with multi-system involvement such as ochronotic arthropathy, renal, urethral and prostatic calculi, cardiac valvular lesions and pigmentation of the skin, sclera, cartilage and other connective tissues. An association of the disease with uveitis has never been reported. We report the first case of alkaptonuria with ochronotic arthropathy presenting with recurrent acute anterior uveitis as the initial manifestation. The possible common link with the HLA-B27 gene is discussed.
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John S S, Padhan P, Mathews J V, David S. Acute anterior uveitis as the initial presentation of alkaptonuria.J Postgrad Med 2009;55:35-37
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John S S, Padhan P, Mathews J V, David S. Acute anterior uveitis as the initial presentation of alkaptonuria. J Postgrad Med [serial online] 2009 [cited 2023 Mar 30 ];55:35-37
Available from: https://www.jpgmonline.com/text.asp?2009/55/1/35/48438
Alkaptonuria is a rare autosomal recessive metabolic disorder that affects approximately one in one million individuals.  The disease may present with multi-system involvement such as ochronotic arthropathy, renal, urethral and prostatic calculi, cardiac valvular lesions and pigmentation of the skin, sclera, cartilage and other connective tissues. The vertebral changes in ochronotic arthropathy closely resemble seronegative spondyloarthropathy and have been linked to the HLA-B27 genotype.  Although the association of acute anterior uveitis with the seronegative spondyloarthropathies and the HLA-B27 gene has been widely studied,  uveitis has never been reported to be associated with alkaptonuria. We report the first case of alkaptonuria with ochronotic arthropathy presenting with recurrent acute anterior uveitis as the initial manifestation.
A 48-year-old man with recurrent episodes of acute, unilateral alternating, non-granulomatous anterior uveitis was referred to the uveitis clinic for evaluation. The patient had the first episode of acute anterior uveitis in the right eye two years ago. This was followed six months later, by a similar episode in the left eye. He was referred to the uveitis clinic when he presented with the third episode.
He also complained of stiffness in his lower back for the past ten years and found it difficult to get up from the squatting position. He had been born of a second-degree consanguineous marriage. His mother and paternal grandmother had permanent spinal deformities at a young age.
On examination, the best-corrected visual acuity was 6/9 in the right eye and 6/6 in the left eye. He had acute anterior uveitis in the right eye [Figure 1]. The left eye had posterior synechiae and pigment deposits on the lens, indicative of previous episodes of anterior uveitis [Figure 2]. There was some black pigmentation of the sclera in both eyes [Figure 3]. On physical examination, he had limitation of spinal movements. In view of the presentation of recurrent acute anterior uveitis in the presence of an obvious spinal involvement and a positive family history, he was provisionally diagnosed as a case of ankylosing spondylitis. Other causes of uveitis like sarcoidosis, tuberculosis, syphilis and HIV infection were ruled out.
The X-rays of the sacroiliac joints and the lumbosacral spine showed calcification of multiple intervertebral discs without any evidence of sacroiliitis [Figure 4], which was very atypical of ankylosing spondylitis. When the patient was examined again, he was found to have some dark pigmentation on both pinnae and on the fingertips, which was initially missed due to the dark color of his skin [Figure 5]. He also had some thickening of the tendoachilles in the left leg [Figure 6]. Hence, the possibility of ochronotic spondyloarthropathy was considered. The black pigmentation of the sclera also pointed to this diagnosis. Urine test for homogentisic acid was ordered. It was reported to be positive using the paper chromatography method. Ultrasound scan of the abdomen showed small hyperechoic foci suggestive of calcification in the prostate gland, the largest measuring four millimeters. There was no evidence of renal calculi. Echocardiography was normal. He tested positive for the HLA-B27 antigen.
He was finally diagnosed as a case of alkaptonuria with ochronotic spondyloarthropathy. He was counseled about the nature of his disease, advised dietary protein restriction and started on physiotherapy and high-dose ascorbic acid. The uveitis in the right eye subsided with topical steroids and cycloplegics, and at the last follow-up visit one year later, his vision was 6/6 in both eyes.
Alkaptonuria is a rare autosomal recessive disorder of phenylalanine and tyrosine metabolism caused by deficiency in homogentisate 1,2-dioxygenase activity, leading to accumulation of large amounts of homogentisic acid in the body.  It is deposited as an oxidized and polymerized pigment (ochronotic pigment) in various tissues and organs, binding irreversibly to collagen and causing bluish-black pigmentation (ochronosis). Homogentisic acid is also excreted in urine, turning dark brown or black upon oxygenation and alkalinization. Ochronotic spondyloarthropathy is the most common complication of alkaptonuria, affecting the spine and the large weight-bearing joints, and later the shoulders.  It occurs due to deposition of the ochronotic pigment in the intervertebral discs and articular cartilage of the large joints. Tendon and ligament ruptures occur with minimal provocation. Thickening of the tendoachilles, as seen in our patient, is also a feature of alkaptonuria.  Ochronotic spondyloarthropathy resembles ankylosing spondylitis in its particular damage to the spine and large joints, but differs in sparing the sacroiliac joint. The spinal involvement results in kyphosis, height loss and decreased lumbar flexion, and the joint disease decreases the range of motion and causes effusions.  The posture and stance (spinal deformity and forward stoop) of a patient with ochronotic spondyloarthropathy are also similar to that of a patient with ankylosing spondylitis. However, unlike ankylosing spondylitis, bamboo spine, annular ossification, syndesmophytes, erosion, and fusion of sacroiliac joints do not occur in ochronotic spondyloarthropathy. 
Although alkaptonuria is not one of the diseases that are classically associated with the HLA-B27 gene, there have been a few case reports suggesting the existence of a possible link between the disease and the gene. The HLA-B27 gene has been associated with the development of ochronotic arthropathy in alkaptonuria.  It has also been claimed that ochronotic arthropathy, especially axial involvement, is more severe in HLA-B27-positive individuals.  Moreover, ochronotic arthropathy closely resembles the changes seen in seronegative spondyloarthropathy.  Coexistence of ochronosis with ankylosing spondylitis  has also been reported.
The association between the HLA-B27 gene, acute anterior uveitis and the seronegative spondyloarthropathies was originally described in 1973 and remains one of the strongest HLA-disease associations to date.  HLA-B27 acute anterior uveitis is defined as inflammation of the anterior segment of the eye occurring in association with the HLA-B27 antigen. It is characterized by recurrent episodes of acute, fulminant, non-granulomatous, anterior uveitis, with typically unilateral alternating eye involvement, more commonly seen in young men.  The clinical presentation of our case with recurrent, acute, unilateral alternating, non-granulomatous anterior uveitis associated with a spinal deformity was consistent with the classical description of a case of ankylosing spondylitis-related uveitis.
Reports of ocular involvement in alkaptonuria have been limited to black pigmentation of the sclera. There have been no reports of uveitis associated with alkaptonuria to date. Since the HLA-B27 gene has been strongly associated with acute anterior uveitis and possibly associated with ochronotic spondyloarthropathy in alkaptonuria, it could be postulated that the gene acted as a common link between the two diseases in our case, and produced a clinical picture that had an uncanny resemblance to ankylosing spondylitis and associated acute anterior uveitis.
Ochronotic spondyloarthropathy occurring in association with acute anterior uveitis, as in our case, strongly mimics ankylosing spondylitis. Differentiation of the two diseases is imperative as the management is radically different. The treatment of ankylosing spondylitis involves a range of pharmacological agents including immunomodulators and biologics,  while there is no specific treatment available for alkaptonuria at present. Dietary protein restriction and high-dose ascorbic acid have been advocated, but their benefit is controversial.  Nitisinone, a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase, reduces production and urinary excretion of homogentisic acid. However, the long-term efficacy and side-effects of such therapy are unknown. Identifying the gene for alkaptonuria offers the potential for a new therapeutic approach (replacement therapy with a recombinant enzyme) in the treatment of alkaptonuric ochronosis. The disorder does not usually affect lifespan. Surveillance for cardiac, renal and prostate complications is recommended.  Early recognition and appropriate symptomatic and supportive treatment may significantly improve the quality of life in these patients. Physiotherapy, analgesia, and adequate anti-osteoporotic therapy are essential to prevent further disability in patients with ochronotic arthropathy. In advanced cases, surgical replacement of joints and aortic valves results in significant improvement. 
This is the first reported case of acute anterior uveitis associated with alkaptonuria and ochronotic arthropathy. Maintaining a high index of suspicion in such a clinical setting is imperative to avoid misdiagnosis of the condition as ankylosing spondylitis.
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