Alkaptonuria.

A case of alkaptonuria, a rare disorder with autosomal recessive inheritance, is reported here. The patient had palmar pigmentation in addition to the usual features of alkaptonuria.

Introduction

Alkaptonuria is a rare inherited disorder that occurs due to deficiency of homogentisic acid oxidase, resulting in the triad of dark-colored urine, ochronosis, and ochronotic arthropathy. Life expectancy is usually normal. The incidence of alkaptonuria is 1 in 250000 to 1 in 1000000 live births.[1] Only a few cases have been reported from India.

Case Report

A 51-year-old man reported to us with complaints of discoloration of the eyes for 4 years and discoloration of his palms for 2½ years. He had been suffering from backache and pain in the left knee for 20 years. Since childhood he had noticed that his urine turned dark upon standing. He was born of a second-degree consanguineous marriage and was third in the birth order. The family history was not contributory.

On examination, black pigmentation was seen on the sclera bilaterally, midway between the cornea and the inner canthus and also between the cornea and the outer canthus [Figure 1]. Discoloration of the pinna was present [Figure 2]. There was scaling and black pigmentation over both palms, along with pits in the tips of the fingers and relative sparing of the center [Figure 3]. The oral mucosa was normal. The patient was short statured and had kyphoscoliosis. Examination of the spine revealed restriction of movements in all directions. All movements were restricted in both hips and the left knee. Chest expansion was within normal limits. Systemic examination was normal.

Figure 1

Pigment deposition in the sclera – Osler's sign

Figure 2

Pigmentation of the ear

Figure 3

Pigmentation along with pits involving the margins of the palms and tips of the fingers

Urine examination showed the presence of homogentisic acid. Radiological examination of the spine showed reduction in all disc spaces, with calcification of all intervertebral discs. Radiological examination of the pelvis showed bilateral sacroilitis.

Biopsy taken from the left hypothenar eminence showed deposition of ochronotic pigments in the dermis, with disruption of the collagen fibers [Figure 4]. His blood parameters, liver functions tests, renal function tests, ECG, ECHO, and USG abdomen were normal.

Figure 4

Biopsy picture showing pigment deposits in the dermis with a characteristic ochre color

Discussion

Alkaptonuria, an autosomal recessive disorder, was first described by Garrod in 1902.[2] In 1908, Garrod coined the term ′inborn error of metabolism′ and proposed that alkaptonuria resulted from the deficiency of an enzyme that normally splits the aromatic ring of homogentisic acid. The deficient enzyme was identified by La Du et al. in 1958.[3] Pollak et al. mapped the alkaptonuria gene to the chromosome 3q2. Sixty-seven mutations of the alkaptonuria gene have been identified upto date.

Alkaptonuria is due to the deficiency of homogentisic acid oxidase, resulting in accumulation in the tissues of homogentisic acid, an intermediate metabolite of phenylalanine and tyrosine metabolism. As homogentisic acid accumulates both intracellularly and extracellularly, it is oxidized to benzoquinone acetate, which polymerizes to form melanin-like polymers, resulting in widespread deposition in fibrous tissue and cartilage. Some of the homogentisic acid is excreted in the urine. Since homogentisic acid has affinity to alkalis, it was named as alkapton and the condition as alkaptonuria.[4]

One of the first symptoms of alkaptonuria is darkening of urine on standing (due to the oxidation of homogentisic acid). In most pediatric patients, darkening of urine is the only feature suggesting alkaptonuria.[5] The patients are usually asymptomatic until the 3rd decade. Scleral pigmentation (Osler's sign) usually starts around the 3rd decade. Skin pigmentation becomes obvious in the 4th decade. Pigmentation is more in areas exposed to light and where sweat glands are located. One of the first sites to be affected is the ear cartilage. There may be discoloration of the forehead, cheeks, axilla, genitalia, palms, and soles.[4] Brown staining of the nails is seen. Histopathology shows ochronotic pigment deposits within collagen bundles, leading to swelling and homogenization of the bundles. Some bundles show jagged or pointed ends. The ochronotic pigment deposits in the dermis show a yellow or ochre color in sections stained with hematoxylin and eosin, from where ochronosis derives its name.

Ochronotic arthropathy starts around the 4th decade. Weight-bearing joints like the knees and the intervertebral joints in the spine, as well as the shoulder joints, are involved, with narrowing of joint spaces and disc calcifications. Arthritis is the only disabling effect of this condition and occurs in almost all patients as age advances.[4] Ochronotic arthropathy can be so severe as to require total joint replacement. Pigment deposits can be seen in the larynx, tonsils, esophagus, dura mater, eardrums, trachea, and bronchi. Aortic or mitral valvulitis, calcification of coronary arteries and atherosclerotic plaques are seen after the age of 50 years. Pigment deposits can form stones in the prostate, urethra, and kidneys due to high urinary homogentisic acid excretion. The endocrine organs, central nervous system and teeth can also be affected.

The diagnosis is confirmed by the identification and quantification of homogentisic acid in urine using gas-liquid chromatography. The levels of homogentisic acid are increased in the blood, urine, and tissues. Screening for mutations is done after extracting the genomic DNA from whole blood and subjecting it to PCR.[1]

Active surveillance for cardiac, renal, and prostate complications should be done after the 4th decade. No effective therapy is available for the treatment of alkaptonuria at present. Dietary restriction of phenylalanine and tyrosine play a limited role in reducing the excretion of homogentisic acid. Foods to be avoided include milk, meat, poultry, egg, cheese, and nuts. Diet may prevent further progression of arthropathy.

Vitamin C (ascorbic acid), an antioxidant given in the dose of 500 mg twice daily, inhibits the polymerization of homogentisic acid and can be prescribed, but its efficacy has not been proven.

Nitisinone, a triketone herbicide, has shown to significantly reduce the excretion of homogentisic acid by inhibiting the enzyme 4-hydroxy phenylpyruvate dioxygenase that is responsible for the synthesis of homogentisic acid. Side effects include elevated levels of tyrosine and corneal irritation. Long-term studies are needed regarding its safety profile and efficacy.[6]