Alkaptonuria is a genetically determined metabolic disorder characterized by a congenital deficiency of the homogentizinase enzyme and leading to incomplete cleavage of homogentizic acid, its excretion with urine and deposition of this metabolite in tissues (skin, articular cartilage, tendons, sclera, etc.). Signs of alkaptonuria appear in childhood and include the release of urine rapidly darkening in the air, pigmentation of the skin and sclera, osteoarthritis, nephrolithiasis, hoarseness of voice, dysphagia, etc. The diagnosis of alkaptonuria is established taking into account clinical manifestations and laboratory tests (biochemical examination of urine, analysis of synovial fluid), radiography, arthroscopy. Treatment of alkaptonuria is symptomatic (diet therapy, vitamin C, chondroprotectors, NSAIDs, balneotherapy); if necessary, prosthetics of joints or heart valves are performed.
ICD 10
70.2 Tyrosine metabolism disorders
General information
Alkaptonuria (homogentizine aciduria, hereditary ochronosis) is a hereditary pathology of metabolism, which is based on a violation of tyrosine metabolism, leading to excessive formation of an intermediate metabolite – homogentizic acid. The accumulation of homogentizic acid in the body and its excretion in the urine determine the course of the symptom complex known as alkaptonuria. Since the disease is accompanied by a polysystemic lesion, it is of practical interest for a number of medical disciplines: rheumatology, dermatology, orthopedics, urology, cardiac surgery, genetics, etc. Alkaptonuria is rare, with a frequency of 1:250 thousand-1:1 million people in the world. To a greater extent, pathology is common among the male population of the Dominican Republic, Germany, the Czech Republic, Slovakia, India, and the USA.
Causes of alkaptonuria
Alkaptonuria is one of the genetically determined enzymopathies inherited by an autosomal recessive type, i.e. for the development of clinical manifestations of the disease, a child must receive from each of the parents one copy of the mutant gene. In alkaptonuria, mutations affect the homogentizic acid oxidase (HGD) gene localized on the long arm of chromosome 3 (3q 21-23). As a result, the reproduction of the enzyme homogentizinase (homogentizine oxidase), which is involved in the cleavage of tyrosine and phenylalanine, is disrupted.
Normally, homogenizic acid, which is an intermediate metabolite of tyrosine and phenylalanine metabolism, under the action of homogenizinase is transformed into maleylacetoacetic acid and further cleaved to acetoacetic and fumaric acids, which then participate in subsequent biochemical cycles. With alkaptonuria, in conditions of congenital enzyme deficiency, homogentizic acid does not undergo further metabolism, but turns into quinone polyphenols (alkapton pigment), which accumulate in connective tissues and are excreted in large quantities in the urine (up to 4-8 g per day).
Symptoms of alkaptonuria
Alkaptonuria is characterized by the following main symptom complexes: homogentizine aciduria, ochronosis and arthropathy. These signs occur at different times: urine staining exists from birth, tissue pigmentation becomes pronounced by the age of 30, joint damage develops in the fourth decade of life.
Early signs of alkaptonuria can be noticed even in early childhood: dark stains from urine remain on the wet diapers of the child, which cannot be washed off. Due to the large amount of homogentizic acid, the collected urine also quickly acquires a dark brown color during settling. In the future, pyelonephritis, urolithiasis, calculous prostatitis often develop from the genitourinary organs.
The skin syndrome with alkaptonuria is characterized by the appearance of gray-brown pigmentation on the face (in the area of the back of the nose, around the lips and eyes), on the neck, palms, abdomen, axillary and inguinal areas. A typical sign of alkaptonuria is the compaction and gray-blue staining of the auricles, pigmentation of the sclera and conjunctiva. Diffuse deposition of pigment is noted in the cartilages of the larynx, which is accompanied by hoarseness of voice, shortness of breath, dysphagia and pain when swallowing. Over time, calcification of the aorta and heart valves develops, resulting in atherosclerosis, acquired aortic and mitral defects. In severe forms of alkaptonuria, pigment deposition can occur in the thyroid gland, adrenal glands, testicles, pancreas, spleen.
The lesion of the musculoskeletal system mainly affects the large joints of the lower extremities and the spine. First of all, changes in the type of deforming spondylosis develop in the lumbar, then in the thoracic spine. At the same time, the smoothness of lumbar lordosis, pain and stiffness during movements gradually increases, up to a complete loss of mobility in the affected parts of the spine. Following the defeat of the spine, signs of deforming osteoarthritis of the knee, shoulder and hip joints appear. Arthralgia, joint swelling (reactive synovitis), crepitation, mobility, development of flexion contractures are characteristic. Often, with alkaptonuria, the sacroiliac joints and the pubic joint are affected.
Diagnostics
Most often, alkaptonuria is diagnosed in early childhood, but in some cases it can be detected only as the full symptom complex develops. It is important to indicate the excretion of urine, darkening in the air; the presence of pigmentation and compaction of the skin; progressive damage to the spine and joints. The correct diagnosis is facilitated by instrumental (X-ray, ultrasound, endoscopic) and laboratory examination. In order to assess concomitant disorders of alkaptonuria, patients need to consult a rheumatologist, orthopedist, dermatologist, urologist, nephrologist, cardiologist, ophthalmologist.
During radiography of the spine, signs of chondrocalcinosis of the intervertebral discs and osteosclerosis of the vertebral bodies, narrowing of the intervertebral slits are revealed. Ultrasound and radiography data of large joints are characterized by narrowing of articular gaps, osteosclerosis, the presence of osteophytes and free intraarticular bodies, ossification of cartilage and periarticular tissues. Diagnostic arthroscopy of the knee and hip joints with alkaptonuria allows you to detect a characteristic pigmentation of cartilage. Kidney and prostate stones are detected during pyelography, ultrasound of the kidneys and prostate. The condition of the heart valves and blood vessels is clarified during EchoCG, aortic ultrasound. During laryngoscopy, you can see the dark color of the laryngeal cartilage.
The pathogenetic diagnosis of alkaptonuria involves a biochemical examination of urine using the method of enzymatic spectrophotometry or liquid chromatography and the determination of homogentizic and benzoquinoacetic acids in it. Evaluation of the color of urine allows you to notice its significant darkening when in the air, heating and alkalizing. Some help can be provided by the study of synovial fluid, which has no signs of inflammation, but contains particles of ochronotic pigment. Changes specific to alkaptonuria are found in the synovial membrane obtained by joint biopsy.
Differential diagnosis
Differential diagnosis of alkaptonuria should be carried out with osteochondrosis, Bekhterev’s disease, porphyria, amyloidosis, argyrosis, lipoproteinosis, etc. The genetic form of the disease should be distinguished from symptomatic alkaptonuria caused by hypovitaminosis C – the latter disappears after the appointment of large doses of ascorbic acid.
Treatment of alkaptonuria
Etiopathogenetic therapy of genetic alkaptonuria has not been developed to date. To prevent excessive formation of homogentizic acid, some authors point to the expediency of following a low-protein diet. In order to improve tyrosine metabolism in alkaptonuria, vitamin C intake is indicated . Basically, drug therapy of alkaptonuria is symptomatic and includes the use of nonsteroidal anti-inflammatory drugs, antispasmodics, chondroprotectors; intra-articular administration of hydrocortisone, hyaluronic acid. Balneo-physiotherapy procedures (radon baths, mud therapy, paraffin applications), massage, physical therapy have a positive effect.
In case of significant deformation of the joints, the issue of orthopedic surgical correction – endoprosthetics of knee, hip or shoulder joints is solved. In case of hemodynamically significant damage to the heart valves, mitral or aortic valve replacement is performed.
Forecast
The prognosis for the cure of alkaptonuria is unfavorable. The disease has a chronic progressive course with the development of irreversible changes in the body. The outcome of alkaptonuria is persistent disability of the patient. The genetic nature of the pathology does not allow us to talk about the possibility of specific prevention. To predict the development of alkaptonuria in offspring, it is recommended to consult a geneticist.
