|Year : 2014 | Volume
| Issue : 2 | Page : 125-129
Alkaptonuria with review of literature
Onteddu Joji Reddy, Jamkhana Abdul Gafoor, Balla Suresh, Polysetty Obuleswar Prasad
Department of Radiology, Government General Hospital, Bhudhawarapeta, Kurnool, Andhra Pradesh, India
|Date of Web Publication||20-Jun-2014|
Onteddu Joji Reddy
Department of Radiology, Government General Hospital, Bhudhawarapeta, Kurnool-518 003, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Alkaptonuria, a metabolic disorder characterized by a triad of homogentisic aciduria, arthritis, and ochronosis is one of the first conditions in the group of inborn errors of metabolism proposed to have Mendelian recessive inheritance. It is due to the deficiency of the enzyme homogentisic acid (HGA) oxidase which catalyzes the conversion of HGA to maleylacetoacetic acid in the catabolism of tyrosine. HGA thus accumulates in cells and body fluids and its oxidized polymers bind to collagen, leading to progressive deposition of grey to bluish black pigment resulting in degenerative changes in cartilage, intervertebral disc, and other connective tissues, leading to arthritis which is the only disabling effect in an affected older individual. However, the diagnosis can be made in neonates when blackish stain is noticed in an unwashed diaper. In this report we describe a 46-year-old male patient who presented with typical features of alkaptonuria.
Keywords: Alkaptonuria, ochronosis, ochronotic arthritis
|How to cite this article:|
Reddy OJ, Gafoor JA, Suresh B, Prasad PO. Alkaptonuria with review of literature. J NTR Univ Health Sci 2014;3:125-9
| Introduction|| |
Alkaptonuria, a metabolic disorder characterized by a triad of homogentisic aciduria, arthritis, and ochronosis is one of the first conditions in the charter of group of inborn errors of metabolism proposed to have Mendelian recessive inheritance. It is due to the deficiency of the enzyme homogentisic acid (HGA) oxidase which catalyzes the conversion of HGA to maleylacetoacetic acid in the catabolism of tyrosine. HGA thus accumulates in cells and body fluids and its oxidized polymers bind to collagen, leading to progressive deposition of grey to bluish black pigment resulting in degenerative changes in cartilage, intervertebral disc, and other connective tissues, leading to arthritis which is the only disabling effect in an affected older individual. However, the diagnosis can be made in neonates when blackish stain is noticed in an unwashed diaper.
| Case report|| |
A 46-year-old male patient was attended with the chief complaints of swelling and pain in both knee joints since 10 years. The pain and swelling are progressive in nature. Patient was unable to walk without support and had difficulty in sitting and standing. He had undergone cervical laminectomy (C3-C6) and lumbar laminectomy (L2-L5) for degeneration of intervertibral discs causing nerve root compression 2 years back. Patient had noticed blackish discoloration of undergarments after urination since childhood and he does not observe change of any color of urine after voiding. He was taking regular analgesics without any benefit for knee pains. He was the product of nonconsanguineous marriage and he was the elder brother of four younger sisters and one younger brother. There were no similar complaints in family members. On examination, there was swelling of both knee joints with painful restriction of all range of movements around the knee. Then we took the X-rays of knee joints and dorsolumbar spine which showed degenerative changes such as joint space narrowing, osteophyte formation, loose bodies, subchondral sclerosis, and extensive soft tissue calcifications noted in anterolateral compartment of both knee joints [Figure 1]. The lumbar lateral X-ray showed extensive diffuse intervertibral disc calcifications at multiple levels with vaccum phenomenon, disc space narrowing, marginal osteophytes, and superior and inferior end plate changes of all dorsolumbar vertebral levels [Figure 2] and [Figure 3]. The cervical spine showed degenerative changes with laminectomy of C2-C6 [Figure 4]. The shoulder's X-ray also showed joint space narrowing, subchondral cysts with degenerative changes on both sides [Figure 5]a and b. The pelvis with hip showed mild sclerosis of actabular roof in superolateral compartment on both sides [Figure 6]. The X-rays of both ankles with lower legs showed linear soft tissue calcifications parallel to leg bones [Figure 7]a and b. In ultrasound examination large multiple (2.5 cm) prostatic calculi are visualized [Figure 8] and [Figure 9]. With these history and imaging findings ankylosing spondilitis, alkaptonuria, and hyperparathyroidism are considered as differential diagnosis. The patient's urine color was changed to dark brown on long standing [Figure 10]. The following biochemical tests were done for urine homogentisic acid (HGA) levels:
|Figure 1: X ray both knee joints anteroposterior view showing degenerative changes at articular surfaces with joint space narrowing and calcifications in soft tissues anterolateral to knee joint|
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|Figure 2: X-ray lumbar spine lateral view showing diffuse intervertibral disc calcification at multiple levels with vaccum phenomenon|
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|Figure 3: X-ray dorsolumbar spine shows intervertebral disc calcifications at multiple levels with degenerative changes|
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|Figure 4: X-ray cervical spine lateral view showing minimal spondylosis changes with laminectomy|
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|Figure 6: X-ray pelvis showing irregularity at superolateral acetabulum on both sides indicating early degenerative changes|
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|Figure 7: (a and b) X ray of both ankles lateral view showing linear soft tissue calcifications and irregularity of calcaneum at insertion of achillies tendon indicating enthesopathy|
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|Figure 10: A clear urine sample immediately after passing and change in color to dark brown after 2 h of exposure|
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- Urine turned black with the addition of sodium hydroxide or exposure to air for many hours.
- Ferric chloride test: Formed transient green color.
- Ammoniacal silver nitrate test: Formed black precipitate of silver.
- Benedict's test: Dark supernatant, initial greenish brown precipitate followed by a yellow precipitate of cuprous oxide on standing.
The urine sent to National Reference Laboratory for HGA levels showed very high urinary HGA levels through gas liquid chromatography. Patient's serum calcium, phosphorous, and parathyroid hormone levels were within normal limits. Two-dimensional (2D) echo was done to rule out any heart valvular calcifications and vegetations which showed only mild tricuspid regurgitation with normal leaflets of all heart valves. With these imaging findings, clinical history, and biochemical laboratory investigations we diagnosed this rare case of alkaptonuria.
| Discussion|| |
Alkaptonuria is a very rare hereditary disease of aromatic amino acids metabolism. It has the distinction of being the first disease in which a Mendelian recessive inheritance pattern was proposed and described under the heading of 'inborn errors of metabolism'. The Egyptian mummy Harwa, dating from 1500 BC, had alkaptonuria, but the term "alcapton" was first used in 1859 by Boedecker to describe a patient's urinary reducing compound, later identified as 2,5-dihydroxyphenylacetic acid, or HGA by Wolkow and Baumann in 1891.  In his Croonian lectures of 1908, Garrod coined the term "inborn error of metabolism" and proposed that alkaptonuria results from a deficiency of an enzyme that normally splits the aromatic ring of HGA and the deficient enzyme was identified by La Du, et al in 1958.  Pollak et al., located the alkaptonuric gene to 3q2 in a 16-cM region. So far, 67 genetic missense mutations of the alkaptonuria gene have been identified. A review of cases of alkaptonuria throughout the world noted that approximately 600 cases had been described through 1962. It is estimated that the current incidence of alkaptonuria is 1 case in 250,000 to 1 million live births. This metabolic disorder occurs worldwide, with the highest frequency seen in the Czech Republic and Santo Domingo, in which the prevalence approaches 1 case per 25,000 inhabitants. Cases have also been reported from USA, UK, Germany, Lebanon, Sudan, Saudi Arabia, Pakistan, Turkey, and other parts of the world.  There are isolated cases reported sporadically from India.  Parikh et al., reviewed seven cases of alkaptonuria seen over a 6 year period at a genetic clinic in Mumbai. 
In alkaptonuria HGA is converted into benzoquinone acetic acid and polymerized. Ochronosis is the result of binding and chemical reaction of benzoquinone and its polymers with connective tissue.  Typical sites of ochronotic pigment deposition are the eyes, skin, skeletal cartilage, and virtually all collagen rich organs.  Other systems that may be involved include the auditory, genitourinary, cardiovascular, and respiratory tracts. ,, Cardiac involvement occurs due to deposition of polymerized HGA in aortic, mitral, and pulmonic valve. It usually leads to rigidity and calcification.  Chronic progressive joint destruction is associated with pigmentation of connective tissue. Pigmented cartilage is brittle and frequently develops fissures with cellular proliferation, leading to degenerative arthropathy. Pigment may be deposited in tendon attachments as well as in the involved joints. 
There are no roentgen changes early in the disease. In the second and third decade the most distinctive finding is the laminated calcification of multiple intervertebral discs. Commonly all the interspaces are affected and dramatically emphasized by the osteoporosis in the adjoining vertebrae. Universal calcified discs and osteoporosis in young individual are pathognomonic of ochronosis.  The radiographic picture in the spine in Ochronosis is characteristic. Pigment is deposited in annular fibrosis and nucleus pulposus of multiple intervertebral disc spaces causing calcification and ossification in thoracolumbar region.  Various causes of intervertebral disc calcification include ochronosis, calcium pyrophosphate dihydrate (CPPD) crystal deposition disease, acromegaly, hemochromatosis, hyperparathyroidism, poliomyelitis, amyloidosis, and spinal fusion.  This is frequently associated with vacuum phenomenon and subchondral sclerosis.  Vacuum phenomenon is a radiological appearance involving spine in which linear or circular radiolucent collection appears within intervertebral discs. Vacuum phenomenon is a reliable indicator of disc degeneration and is very rare in presence of discal infection or tumor. It is seen in various diseases including intervertebral osteochondrosis, intraspinal disc herniation, spondylosis deformans, Schmorl's nodes, osteoarthritis, and ischemic necrosis.  The disc spaces are very narrow. Spur formation is not particularly prominent. The sacroiliac joints are usually spared. Calcification, subchondral bone destruction, and fusion of symphysis pubis may be seen. Involvement of enthesis (bone tendon interface) may be seen with periostitis in the regions of trochanters, calcaneus, and pelvis. Marked destructive changes are frequent in the knees, shoulders, and hips; but rare in more peripheral joints. The arthropathy is usually associated with rapid joint destruction. Osteophytes and subchondral cysts are rarely as large as those seen with osteoarthritis. Intra-articular calcium pyrophosphate crystals may be seen in close relation to the pigment deposition in large joints.  Degenerative changes occur in shoulder joint. Since osteoarthritis is rare in shoulder it suggests ochronosis in young patients. Cartilage destruction produces joint space narrowing, secondary eburnation, and spur formation at glenoid. Hypertrophic changes occur at humeral head, which may be flattened. Small calcifications occur in periarticular soft tissue. The small joints of extremities usually show only periarticular swelling without significant narrowing of joint space. In older patients massive lipping and ankylosis of spine results in severe dorsal kyphosis with a decrease in lumbar lordosis. 
Currently, symptomatic treatment of the complications of alkaptonuria is the only option. So active surveillance for cardiac, renal, and prostate complications after the 4 th decade of life should be done.  There are anecdotal reports that a diet low in protein especially in amino acids, phenylalanine, and tyrosine can help delay joint problems. Vitamin C, an antioxidant given in the dose of 500 mg twice a day to reduce connective tissue damage has been tried. It partially ameliorates the condition by impeding the polymerization of HGA.  Ochronotic arthropathy is treated with physiotherapy, analgesia, rest, and prosthetic joint replacement when necessary. Tendon ruptures due to ochronosis have been fixed successfully with primary repair.  Activities are restricted in adult life because of arthritic complaints. However, the average life span of the patient is unchanged and they die of causes comparable with the general population.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]