|Year : 2021 | Volume
| Issue : 2 | Page : 200-203
Alkaptonuria: A hereditary disease which is usually diagnosed in adulthood
Mudita Gupta, Rajni Sharma, Ritu Rani
Departments of Dermatology, Venereology and Leprosy, IGMC, Shimla, Himachal Pradesh, India
|Date of Submission||20-Mar-2020|
|Date of Decision||18-Jul-2020|
|Date of Acceptance||08-Feb-2021|
|Date of Web Publication||26-Aug-2021|
Department of Dermatology, Venereology and Leprosy, IGMC, Shimla, Himachal Pradesh
Source of Support: None, Conflict of Interest: None
Alkaptonuria (AKU) is a multisystemic autosomal recessive disease due to deficiency of enzyme homogentisate dioxygenase leading to accumulation of homogentisic acid. Urine becoming dark on oxygenation or alkalinization is the first symptom but is often ignored. The patient usually presents with pigment deposition in connective tissue and cartilage after the third decade. This pigment deposition not only alters the aesthetics but also leads to alteration in the activity of different tissues due to inflammation and subsequent fibrosis or calcification. We are presenting an adult male who was asymptomatic till 5 years back when he started having backache for which he was taking analgesics off and was diagnosed to be having AKU at the age of 58 years.
Keywords: Alkaptonuria, multisystemic, presenting in adulthood
|How to cite this article:|
Gupta M, Sharma R, Rani R. Alkaptonuria: A hereditary disease which is usually diagnosed in adulthood. Clin Dermatol Rev 2021;5:200-3
| Introduction|| |
Alkaptonuria (AKU) is a rare, autosomal-recessive disorder of phenylalanine/tyrosine metabolism. Mutation in 3q2 leads to the deficiency of the enzyme homogentisate dioxygenase leading to the accumulation of homogentisic acid (HA). AKU is a multisystemic disease with black colored urine and pigment deposition in the skin, connective tissue and cartilage.
| Case Report|| |
A 58-year-old male was admitted in the medicine ward with complaints of chest pain. The patient was referred to skin OPD due to the presence of bluish colored lesions on the hands. He also complained of low backache for the last 5 years for which he was taking analgesics off and on. On mucocutaneous examination, there was bluish pigmentation on ear, malar area, temporal area, and sclera of both eyes [Figure 1], [Figure 2], [Figure 3]. He also had similar pigmentation on the dorsum of the hand and lateral aspect of the index and medial aspect of both hands. With the suspicion of AKU patient was further investigated. Urine was allowed to stand overnight, the color of which turned black thereafter [Figure 4]. Benedict's test and Fehling test were positive. Hemogram, renal, and liver function tests were within the normal limits. X-ray of the spine showed calcification of lumbar intervertebral discs, reduction of disc spaces and posterior arthrodesis [Figure 5]. Rheumatoid factor was negative; serum uric acid and c-reactive protein were normal. Echocardiography showed aortic stenosis and calcification of the aortic valves. Plain X-ray and ultrasound abdomen were normal. The patient did not agree for skin biopsy and the diagnosis was made based on characteristic features involving the skin, eye and spine, and biochemical tests.'
|Figure 5: X-ray lumbar spine anteroposterior and lateral view showing calcification of intervertebral discs with narrowing of intervertebral space|
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With a clinical diagnosis of AKU Vitamin C 500 mg twice a day was started. Dietary restriction of foods rich in phenylalanine, tyrosine and protein (milk, meat, poultry, egg, cheese, and nuts) was advised. Furthermore, a regular orthopedic, cardiologist, and ophthalmologist workup was advised.
| Discussion|| |
AKU is a rare autosomal recessive disease due to the defective metabolism of tyrosine. In 1859 Boedker et al. found a reducing substance was found in patient's urine which was called alcapton (derived from the Arabic word alkali). This reducing substance was later identified as HA. Sir Archibald Garrod in 1908 proposed that AKU is an inborn error of metabolism and explained the Mendelian principle of inheritance on the basis of this disease. The deficient enzyme was later identified by La Du et al. and mutation at chromosome 3q2 was detected later. The worldwide incidence of AKU is 1:250000 with a preponderance in Czechoslovakia and Germany. There is no sex predilection, but the disease tends to be severe and earlier in onset in males. A new overview map has recently been created that reports 1233 AKU patients worldwide.
Normally phenylalanine gets converted to tyrosine and then to HA. This HA in presence of homogentisate dioxygenase gets converted to maleyl acetoacetate. The deficiency of this enzyme leads to increased plasma HA. HA, after being formed, can either be excreted in the urine, remain elevated in total body water, be tissue bound and get converted to ochronotic pigment. The kidney tries to remove the excess HA. The decreased renal capability of excretion leads to oxidation of HA with the formation of benzoquinone acetic acid which polymerizes into melanin like pigment and gets deposited in cartilage and connective tissue. Hence, renal excretion of HA is beneficial, but at the same time, it may lead to the renal stone formation or kidney failure. HA plasma levels in AKU sufferers range between 0.018 and 0.165 mM in comparison to non-AKU sufferers plasma levels of 0.014–0.071 μM, a thousand-fold difference.
The first symptom of AKU is the darkening of the urine. Fresh urine of AKU patient may be normal. Urine turns black on exposure to air (oxidation of HGA). The process of oxidation is very slow so often not observed by relatives. Alkalization of urine may speed up the process. HA being a strong reducing agent may show positivity with Benedict's (dark supernatant with initial greenish brown precipitate followed by a yellow precipitate of cuprous oxide on standing) and Fehling reagent (transient green color).
Later in third-decade ocular deposition of pigment may occur Pigmentation at the insertion of the lateral rectus muscle is visible in the sclera (Osler's sign) there are four main types of appearance which may also be seen vermiform, tube-like, brown pinguecula-like, dot-like or laminar.
Skin pigmentation usually appears a decade later. As pigment has predilection for deposition at cartilage cutaneous discoloration is first visible at concha followed by antihelix and then tragus. Palms, soles, external genitalia with numerous sweat glands and sites of friction are also predisposed for pigment deposition. Mucosal, dorsum of the hand, cheeks, forehead are the other mucocutaneous sites involved. This pigment appears ochre-colored (dark yellow) under hematoxylin and eosin staining, leading to the term ochronosis.
Ochronotic arthropathy manifests in the fourth to fifth decades. Usually involves the weight-bearing joints, especially the knees and spine. Spinal involvement mimics ankylosing spondyloarthritis. Calcified vertebral column with osteoporosis is pathognomonic of AKU Radiography shows universal narrowing of joint space, with osteoporosis, osteophytosis, and calcification in the vertebral column. The calcification of intervertebral discs is pronounced at the periphery and tends to spare the central nucleus pulposus, with its wafer-like pattern. The mechanism of skeletal changes is not very clear. Pigment deposition evokes inflammatory response and increased free radical generation. Cartilage calcification in AKU is much harder than normal cartilage calcification. Ossification of tissues in AKU occurs due to deposition of calcium crystals different from that observed in other forms of pathological ossification Altered biomechanics and biochemical changes due to defective metabolism leads to disturbed metabolism of chondrocytes, alteration of cross-linkage of collagen fibrils (lysyl hydroxylase inhibited by benzoquinone acetic acid) and extracellular matrix. Articular cartilages become stiff and brittle with an increased tendency for fractures.
Other complications of AKU begin after the age of 50 years and include pigment stone formation (renal, prostatic, gall bladder, and salivary) along with cardiac valve involvement, particularly aortic valve disease. Conductive deafness due to involvement of tympanic membrane and ossicles may occur. Increased mechanical forces lead to increased pigmentation. This explains the predominance of ochronosis on frictional site and in arteries compared to veins. Though there is multisystemic involvement three different missense variants of the homogentisate 1,2-dioxygenase genes lead to variability in clinical presentation.
Though the clinical features are characteristic of the disease confirmation can be done by the identification and quantification of HA in urine using gas-liquid chromatography. DNA sequencing can be done to identify the gene.
There is no effective therapy available for the treatment of AKU at present. Symptomatic treatment is usually given. Decreased intake of tyrosine and phenylalanine rich foods (milk, meat, poultry, egg, cheese, and nuts) has limited benefit. Higher dose (1 g/day) of Vitamin C is recommended but not much helpful. The mild anti-oxidant nature of ascorbic acid helps retard the process of conversion of homogentisate to the polymeric material that is deposited in cartilaginous tissues.
Nitisinone, a triketone herbicide, has shown to significantly reduce the excretion of HA by inhibiting the enzyme 4-hydroxy phenylpyruvate dioxygenase that is responsible for its synthesis. HA and tyrosine concentrations have been quantified in AKU before and after treatment with nitisinone in the dose-response study Suitability of Nitisinone in AKU. Side effects include elevated levels of tyrosine and corneal irritation he main leading to corneal keratopathy and opacity. This keratopathy is reversible after 2 weeks of cessation of the drug.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]