Alkaptonuria
Encyclopedia
Alkaptonuria is a rare inherited genetic disorder of phenylalanine
and tyrosine
metabolism. This is an autosomal recessive condition
that is due to a defect in the enzyme
homogentisate 1,2-dioxygenase
, which participates in the degradation of tyrosine. As a result, a toxic tyrosine byproduct called homogentisic acid (or alkapton) accumulates in the blood and is excreted in urine in large amounts (hence -uria). Excessive homogentisic acid causes damage to cartilage
(ochronosis
, leading to osteoarthritis
) and heart valve
s as well as precipitating as kidney stone
s. Treatment with nitisinone
, which suppresses homogentisic acid production, is being studied. Alkaptonuria is more common in Slovakia
and the Dominican Republic
than in other countries.
, but the sclera
of the eyes may be pigmented (often only at a later age), and the skin may be darkened in sun-exposed areas and around sweat gland
s; sweat may be coloured brown. Urine may turn brown if collected and left exposed to open air, especially when left standing for a period of time. Kidney stone
s and stone formation in the prostate
(in men) are common and may occur in more than a quarter of cases.
The main symptoms of alkaptonuria are due to the accumulation of homogentisic acid in tissues. In the joint
s this leads to cartilage damage, specifically in the spine
, leading to low back pain
at a young age in most cases. Cartilage damage may also occur in the hip and shoulder. Joint replacement
surgery (hip and shoulder) is often necessary at a relatively young age.
Valvular heart disease
, mainly calcification and regurgitation of the aortic
and mitral valve
s, may occur, and in severe and progressive cases valve replacement
may be necessary. Coronary artery disease may be accelerated in alkaptonuria.
A distinctive characteristic of alkaptonuria is that ear wax exposed to air turns red or black (depending on diet) after several hours because of the accumulation of homogentisic acid.
and thin layer chromatography
. Both blood plasma and urine can be used for diagnosis. In healthy subjects, homogentisic acid is absent in both blood plasma and urine. In alkaptonuria, plasma levels are 6.6 micrograms/ml on average, and urine levels are on average 3.12 mmol/mmol of creatinine
.
, an amino acid
. Hepatic
homogentisate 1,2-dioxygenase
(coded by the HGD gene) metabolises homogentisic acid into 4-maleylacetoacetate
. Alkaptonuria arises in people who have inherited two abnormal HGD genes: one from each parent. Numerous different HGD mutations have been identified.
In a patient who underwent a liver transplant for an unrelated problem, alkaptonuria resolved and joint disease stabilised after the transplant, confirming that the liver is the main site of homogentisic acid production in alkaptonuria.
and tyrosine and large doses of ascorbic acid
(vitamin C). Dietary restriction may be effective in children, but benefits in adults have not been demonstrated.
The insecticide nitisinone
inhibits 4-hydroxyphenylpyruvate dioxygenase
, the enzyme that generates homogentisic acid from 4-hydroxyphenylpyruvic acid
. This reduces homogentisic acid. The main side-effect is irritation of the cornea
, and there is a concern that it will cause the symptoms of hereditary tyrosinaemia type III
because of the possible accumulation of tyrosine or other intermediaries. Further studies are being conducted.
, but exact prevalence there is not known.
, as being the result of the accumulation of intermediates due to metabolic deficiencies. He linked ochronosis
with the accumulation of alkaptans in 1902, and his views on the subject, including its mode of heritance, were summarised in a 1908 Croonian lecture at the Royal College of Physicians
. The defect was narrowed down to homogentisic acid oxidase deficiency in a study published in 1958. The genetic basis was elucidated in 1996, when HGD mutations were demonstrated.
A 1977 study showed that an ochronotic Egyptian mummy
had probably suffered from alkaptonuria.
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
and tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
metabolism. This is an autosomal recessive condition
Dominance relationship
Dominance in genetics is a relationship between two variant forms of a single gene, in which one allele masks the effect of the other in influencing some trait. In the simplest case, if a gene exists in two allelic forms , three combinations of alleles are possible: AA, AB, and BB...
that is due to a defect in the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
homogentisate 1,2-dioxygenase
Homogentisate 1,2-dioxygenase
Homogentisate 1,2-dioxygenase is an enzyme, which catalyzes the conversion of homogentisate to 4-maleylacetoacetate. Homogentisate 1,2-dioxygenase or HGD is involved in the catabolism of aromatic rings, more specifically in the breakdown of the amino acids tyrosine and phenylalanine...
, which participates in the degradation of tyrosine. As a result, a toxic tyrosine byproduct called homogentisic acid (or alkapton) accumulates in the blood and is excreted in urine in large amounts (hence -uria). Excessive homogentisic acid causes damage to cartilage
Cartilage
Cartilage is a flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs...
(ochronosis
Ochronosis
Ochronosis is the syndrome caused by the accumulation of homogentisic acid in connective tissues. The phenomenon was first described by Rudolf Virchow in 1865. The condition was named after the yellowish discoloration of the tissue seen on microscopic examination...
, leading to osteoarthritis
Osteoarthritis
Osteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...
) and heart valve
Heart valve
A heart valve normally allows blood flow in only one direction through the heart. The four valves commonly represented in a mammalian heart determine the pathway of blood flow through the heart...
s as well as precipitating as kidney stone
Kidney stone
A kidney stone, also known as a renal calculus is a solid concretion or crystal aggregation formed in the kidneys from dietary minerals in the urine...
s. Treatment with nitisinone
Nitisinone
Nitisinone is a drug originally developed as an herbicide now used in the treatment of hereditary tyrosinemia type 1. Since its first use for this indication in 1991, it has replaced liver transplantation as the first-line treatment for this rare condition...
, which suppresses homogentisic acid production, is being studied. Alkaptonuria is more common in Slovakia
Slovakia
The Slovak Republic is a landlocked state in Central Europe. It has a population of over five million and an area of about . Slovakia is bordered by the Czech Republic and Austria to the west, Poland to the north, Ukraine to the east and Hungary to the south...
and the Dominican Republic
Dominican Republic
The Dominican Republic is a nation on the island of La Hispaniola, part of the Greater Antilles archipelago in the Caribbean region. The western third of the island is occupied by the nation of Haiti, making Hispaniola one of two Caribbean islands that are shared by two countries...
than in other countries.
Signs and symptoms
Alkaptonuria is often asymptomaticAsymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
, but the sclera
Sclera
The sclera , also known as the white or white of the eye, is the opaque , fibrous, protective, outer layer of the eye containing collagen and elastic fiber. In the development of the embryo, the sclera is derived from the neural crest...
of the eyes may be pigmented (often only at a later age), and the skin may be darkened in sun-exposed areas and around sweat gland
Sweat gland
Sweat glands, or sudoriferous glands, are small tubular structures of the skin that produce sweat. There are two kinds of sweat glands:...
s; sweat may be coloured brown. Urine may turn brown if collected and left exposed to open air, especially when left standing for a period of time. Kidney stone
Kidney stone
A kidney stone, also known as a renal calculus is a solid concretion or crystal aggregation formed in the kidneys from dietary minerals in the urine...
s and stone formation in the prostate
Prostate
The prostate is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals....
(in men) are common and may occur in more than a quarter of cases.
The main symptoms of alkaptonuria are due to the accumulation of homogentisic acid in tissues. In the joint
Joint
A joint is the location at which two or more bones make contact. They are constructed to allow movement and provide mechanical support, and are classified structurally and functionally.-Classification:...
s this leads to cartilage damage, specifically in the spine
Vertebral column
In human anatomy, the vertebral column is a column usually consisting of 24 articulating vertebrae, and 9 fused vertebrae in the sacrum and the coccyx. It is situated in the dorsal aspect of the torso, separated by intervertebral discs...
, leading to low back pain
Low back pain
Low back pain or lumbago is a common musculoskeletal disorder affecting 80% of people at some point in their lives. In the United States it is the most common cause of job-related disability, a leading contributor to missed work, and the second most common neurological ailment — only headache is...
at a young age in most cases. Cartilage damage may also occur in the hip and shoulder. Joint replacement
Joint replacement
Replacement arthroplasty [from Greek arthron, joint, limb, articulate, + -plassein, to form, mould, forge, feign, make an image of], or joint replacement surgery, is a procedure of orthopedic surgery in which the arthritic or dysfunctional joint surface is replaced with an orthopaedic prosthesis...
surgery (hip and shoulder) is often necessary at a relatively young age.
Valvular heart disease
Valvular heart disease
Valvular heart disease is any disease process involving one or more of the valves of the heart . Valve problems may be congenital or acquired...
, mainly calcification and regurgitation of the aortic
Aortic valve
The aortic valve is one of the valves of the heart. It is normally tricuspid , although in 1% of the population it is found to be congenitally bicuspid . It lies between the left ventricle and the aorta....
and mitral valve
Mitral valve
The mitral valve is a dual-flap valve in the heart that lies between the left atrium and the left ventricle...
s, may occur, and in severe and progressive cases valve replacement
Valve replacement
Valve replacement surgery is the replacement of one or more of the heart valves with either an artificial heart valve or a bioprosthesis . It is an alternative to valve repair.There are four procedures:...
may be necessary. Coronary artery disease may be accelerated in alkaptonuria.
A distinctive characteristic of alkaptonuria is that ear wax exposed to air turns red or black (depending on diet) after several hours because of the accumulation of homogentisic acid.
Diagnosis
The diagnosis of alkaptonuria needs to be suspected before diagnostic testing can be performed using paper chromatographyPaper chromatography
Paper chromatography is an analytical chemistry technique for separating and identifying mixtures that are or can be colored, especially pigments. This can also be used in secondary or primary colors in ink experiments. This method has been largely replaced by thin layer chromatography, however it...
and thin layer chromatography
Thin layer chromatography
Thin layer chromatography is a chromatography technique used to separate mixtures. Thin layer chromatography is performed on a sheet of glass, plastic, or aluminum foil, which is coated with a thin layer of adsorbent material, usually silica gel, aluminium oxide, or cellulose...
. Both blood plasma and urine can be used for diagnosis. In healthy subjects, homogentisic acid is absent in both blood plasma and urine. In alkaptonuria, plasma levels are 6.6 micrograms/ml on average, and urine levels are on average 3.12 mmol/mmol of creatinine
Creatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
.
Pathophysiology
Homogentisic acid is a natural intermediary of the metabolism of tyrosineTyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
, an amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
. Hepatic
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
homogentisate 1,2-dioxygenase
Homogentisate 1,2-dioxygenase
Homogentisate 1,2-dioxygenase is an enzyme, which catalyzes the conversion of homogentisate to 4-maleylacetoacetate. Homogentisate 1,2-dioxygenase or HGD is involved in the catabolism of aromatic rings, more specifically in the breakdown of the amino acids tyrosine and phenylalanine...
(coded by the HGD gene) metabolises homogentisic acid into 4-maleylacetoacetate
4-Maleylacetoacetate
4-Maleylacetoacetate is an intermediate in the metabolism of tyrosine.-See also:* Homogentisate 1,2-dioxygenase...
. Alkaptonuria arises in people who have inherited two abnormal HGD genes: one from each parent. Numerous different HGD mutations have been identified.
In a patient who underwent a liver transplant for an unrelated problem, alkaptonuria resolved and joint disease stabilised after the transplant, confirming that the liver is the main site of homogentisic acid production in alkaptonuria.
Treatment
No treatment modality has been unequivocally demonstrated to reduce the complications of alkaptonuria. Commonly recommended treatments include dietary restriction of phenylalaninePhenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
and tyrosine and large doses of ascorbic acid
Ascorbic acid
Ascorbic acid is a naturally occurring organic compound with antioxidant properties. It is a white solid, but impure samples can appear yellowish. It dissolves well in water to give mildly acidic solutions. Ascorbic acid is one form of vitamin C. The name is derived from a- and scorbutus , the...
(vitamin C). Dietary restriction may be effective in children, but benefits in adults have not been demonstrated.
The insecticide nitisinone
Nitisinone
Nitisinone is a drug originally developed as an herbicide now used in the treatment of hereditary tyrosinemia type 1. Since its first use for this indication in 1991, it has replaced liver transplantation as the first-line treatment for this rare condition...
inhibits 4-hydroxyphenylpyruvate dioxygenase
4-Hydroxyphenylpyruvate dioxygenase
4-Hydroxyphenylpyruvate dioxygenase HPPD is an Fe-containing enzyme, that catalyzes the second reaction in the catabolism of tyrosine - the conversion of 4-hydroxyphenylpyruvate to homogentisate.-Function:...
, the enzyme that generates homogentisic acid from 4-hydroxyphenylpyruvic acid
4-Hydroxyphenylpyruvic acid
4-Hydroxyphenylpyruvic acid is an intermediate in the metabolism of the amino acid phenylalanine. The aromatic side chain of phenylalanine is hydroxylated by the enzyme phenylalanine hydroxylase to form tyrosine. The conversion from tyrosine to 4-HPPA is in turn catalyzed by tyrosine...
. This reduces homogentisic acid. The main side-effect is irritation of the cornea
Cornea
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...
, and there is a concern that it will cause the symptoms of hereditary tyrosinaemia type III
Type III tyrosinemia
Type III tyrosinemia is a rare disorder caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase , encoded by the gene HPD. This enzyme is abundant in the liver, and smaller amounts are found in the kidneys. It is one of a series of enzymes needed to break down tyrosine...
because of the possible accumulation of tyrosine or other intermediaries. Further studies are being conducted.
Epidemiology
In Slovakia the disease occurs in 1:19,000 people. In other ethnic groups, the normal prevalence is between 1:100,000 and 1:250,000. It is reported frequently in the Dominican RepublicDominican Republic
The Dominican Republic is a nation on the island of La Hispaniola, part of the Greater Antilles archipelago in the Caribbean region. The western third of the island is occupied by the nation of Haiti, making Hispaniola one of two Caribbean islands that are shared by two countries...
, but exact prevalence there is not known.
History
Alkaptonuria was one of the four diseases described by Sir Archibald Edward GarrodArchibald Garrod
Sir Archibald Edward Garrod KCMG, FRS was an English physician who pioneered the field of inborn errors of metabolism.- Education and Personal Life :...
, as being the result of the accumulation of intermediates due to metabolic deficiencies. He linked ochronosis
Ochronosis
Ochronosis is the syndrome caused by the accumulation of homogentisic acid in connective tissues. The phenomenon was first described by Rudolf Virchow in 1865. The condition was named after the yellowish discoloration of the tissue seen on microscopic examination...
with the accumulation of alkaptans in 1902, and his views on the subject, including its mode of heritance, were summarised in a 1908 Croonian lecture at the Royal College of Physicians
Royal College of Physicians
The Royal College of Physicians of London was founded in 1518 as the College of Physicians by royal charter of King Henry VIII in 1518 - the first medical institution in England to receive a royal charter...
. The defect was narrowed down to homogentisic acid oxidase deficiency in a study published in 1958. The genetic basis was elucidated in 1996, when HGD mutations were demonstrated.
A 1977 study showed that an ochronotic Egyptian mummy
Mummy
A mummy is a body, human or animal, whose skin and organs have been preserved by either intentional or incidental exposure to chemicals, extreme coldness , very low humidity, or lack of air when bodies are submerged in bogs, so that the recovered body will not decay further if kept in cool and dry...
had probably suffered from alkaptonuria.