Alkaptonuria is a rare inherited genetic disease which is caused by a

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...

in the ''HGD''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

for the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

homogentisate 1,2-dioxygenase (); if a person inherits an abnormal copy from both parents (it is a recessive condition), the body accumulates an intermediate substance called homogentisic acid in the blood and tissues. Homogentisic acid and its oxidized form ''alkapton'' are excreted in the urine, giving it an unusually dark color. The accumulating homogentisic acid causes damage to

cartilage Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck ...

(

ochronosis Ochronosis is a syndrome caused by the accumulation of homogentisic acid in connective tissues. The condition was named after the yellowish (ocher-like) discoloration of the tissue seen on microscopic examination. Macroscopically, though, the a ...

, leading to

osteoarthritis Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the ...

) and

heart valve A heart valve is a one-way valve that allows blood to flow in one direction through the chambers of the heart. Four valves are usually present in a mammalian heart and together they determine the pathway of blood flow through the heart. A heart ...

s, as well as precipitating as

kidney stone Kidney stone disease, also known as nephrolithiasis or urolithiasis, is a crystallopathy where a solid piece of material (kidney stone) develops in the urinary tract. Kidney stones typically form in the kidney and leave the body in the urine s ...

s and stones in other organs. Symptoms usually develop in people over 30 years old, although the dark discoloration of the urine is present from birth. Apart from treatment of the complications (such as

pain relief Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professional ...

and

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 an arthritic or dysfunctional ...

for the cartilage damage), the drug

nitisinone Nitisinone, sold under the brand name Orfadin among others, is a medication used to slow the effects of hereditary tyrosinemia type 1 (HT-1). Uses Nitisinone is used to treat hereditary tyrosinemia type 1 (HT-1) in patients from all ages, in com ...

has been found to suppress homogentisic acid production, and research is ongoing as to whether it can improve symptoms. Alkaptonuria is a

rare disease A rare disease is any disease that affects a small percentage of the population. In some parts of the world, an orphan disease is a rare disease whose rarity means there is a lack of a market large enough to gain support and resources for discov ...

; it occurs in one in 250,000 people, but is more common in

Slovakia Slovakia (; sk, Slovensko ), officially the Slovak Republic ( sk, Slovenská republika, links=no ), is a landlocked country in Central Europe. It is bordered by Poland to the north, Ukraine to the east, Hungary to the south, Austria to the ...

and the

Dominican Republic The Dominican Republic ( ; es, República Dominicana, ) is a country located on the island of Hispaniola in the Greater Antilles archipelago of the Caribbean region. It occupies the eastern five-eighths of the island, which it shares with ...

Signs and symptoms

Ochronosis, Intervertebral discs Calcification

Patients with alkaptonuria are

asymptomatic In medicine, any disease is classified asymptomatic if a patient tests as carrier for a disease or infection but experiences no symptoms. Whenever a medical condition fails to show noticeable symptoms after a diagnosis it might be considered a ...

as children or young adults, but their urine may turn brown or even inky black if collected and left exposed to open air. Pigmentation may be noted in the cartilage of the ear and other cartilage, and the

sclera The sclera, also known as the white of the eye or, in older literature, as the tunica albuginea oculi, is the opaque, fibrous, protective, outer layer of the human eye containing mainly collagen and some crucial elastic fiber. In humans, and so ...

and corneal limbus of the eye. After the age of 30, people begin to develop pain in the weight-bearing joints of the spine, hips, and knees. The pain can be severe to the point that interferes with activities of daily living and may affect the ability to work. Joint-replacement surgery (hip and shoulder) is often necessary at a relatively young age. In the longer term, the involvement of the spinal joints leads to reduced movement of the rib cage and can affect breathing.

Bone mineral density Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to optical ...

may be affected, increasing the risk of

bone fracture A bone fracture (abbreviated FRX or Fx, Fx, or #) is a medical condition in which there is a partial or complete break in the continuity of any bone in the body. In more severe cases, the bone may be broken into several fragments, known as a '' ...

s, and rupture of tendons and muscles may occur.

Valvular heart disease Valvular heart disease is any cardiovascular disease process involving one or more of the four valves of the heart (the aortic and mitral valves on the left side of heart and the pulmonic and tricuspid valves on the right side of heart). These ...

, mainly calcification and regurgitation of the

aortic The aorta ( ) is the main and largest artery in the human body, originating from the left ventricle of the heart and extending down to the abdomen, where it splits into two smaller arteries (the common iliac arteries). The aorta distributes ox ...

and

mitral valve The mitral valve (), also known as the bicuspid valve or left atrioventricular valve, is one of the four heart valves. It has two cusps or flaps and lies between the left atrium and the left ventricle of the heart. The heart valves are all on ...

s, may occur, and in severe and progressive cases,

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 (homograft from human tissue or xenograft e.g. from pig). It is an alternative to valve repair. __TOC__ Proc ...

may be necessary. Irregularities in the heart rhythm and

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...

affect a significant proportion of people with alkaptonuria (40% and 10%, respectively). Hearing loss affects 40% of people. Also, a propensity to developing

s exists, and eventually also

gallstone A gallstone is a stone formed within the gallbladder from precipitated bile components. The term cholelithiasis may refer to the presence of gallstones or to any disease caused by gallstones, and choledocholithiasis refers to the presence of mi ...

s and stones in the prostate and

salivary gland The salivary glands in mammals are exocrine glands that produce saliva through a system of ducts. Humans have three paired major salivary glands ( parotid, submandibular, and sublingual), as well as hundreds of minor salivary glands. Salivary ...

s ( sialolithiasis) can occur.

Pathophysiology

All people carry in their DNA two copies (one received from each parent) of the gene ''HGD'', which contains the genetic information to produce the enzyme homogentisate 1,2-dioxygenase (HGD) which can normally be found in numerous tissues in the body (liver, kidney, small intestine, colon, and prostate). In people with alkaptonuria, both copies of the gene contain abnormalities that mean that the body cannot produce an adequately functioning enzyme. ''HGD'' mutations are generally found in certain parts (

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

s 6, 8, 10, and 13), but a total of over 100 abnormalities has been described throughout the gene. The normal HGD enzyme is a hexamer (it has six subunits) that are organized in two groups of three (two trimers) and contains an iron atom. Different mutations may affect the structure, function, or solubility of the enzyme. Very occasionally, the disease appears to be transmitted in an autosomal-dominant fashion, where a single abnormal copy of ''HGD'' from a single parent is associated with alkaptonuria; other mechanisms or defects in other genes possibly are responsible in those cases. Inborn errors of metabolism of phenylalanine and tyrosine

Inborn errors of metabolism of phenylalanine and tyrosine

The HGD enzyme is involved in the metabolism (chemical processing) of the

aromatic amino acids An aromatic amino acid is an amino acid that includes an aromatic ring. Among the 20 standard amino acids, the following are classically considered aromatic: phenylalanine, tryptophan and tyrosine. Although histidine contains an aromatic ring, ...

phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amin ...

and

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the G ...

. Normally, these enter the bloodstream through protein-containing food and the natural turnover of protein in the body. Tyrosine is specifically required for a number of functions, such as

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...

s (e.g. thyroxine, the thyroid hormone),

melanin Melanin (; from el, μέλας, melas, black, dark) is a broad term for a group of natural pigments found in most organisms. Eumelanin is produced through a multistage chemical process known as melanogenesis, where the oxidation of the amino ...

(the dark pigment in the skin and hair), and certain proteins, but the vast majority (over 95%) is unused and is metabolized through a group of enzymes that eventually generate

acetoacetate Acetoacetic acid (also acetoacetate and diacetic acid) is the organic compound with the formula CHCOCHCOOH. It is the simplest beta-keto acid, and like other members of this class, it is unstable. The methyl and ethyl esters, which are quite stab ...

and

malate Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms (L ...

. In alkaptonuria, the HGD enzyme cannot metabolize the homogentisic acid (generated from tyrosine) into

4-maleylacetoacetate 4-Maleylacetoacetate (4-maleylacetoacetatic acid) is an intermediate in the metabolism of tyrosine. It is converted to fumarylacetoacetate by the enzyme 4-maleylacetoacetate cis-trans-isomerase. Gluthathione coenzymatically helps in conversion ...

, and homogentisic acid levels in the blood are 100-fold higher than would normally be expected, despite the fact that a substantial amount is eliminated into the urine by the kidneys. The homogentisic acid is converted to the related substance benzoquinone acetic acid which forms

polymer A polymer (; Greek '' poly-'', "many" + '' -mer'', "part") is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic a ...

s that resemble the skin pigment melanin. These are deposited in the

collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whol ...

, a connective tissue protein, of particular tissues such as cartilage. This process is called ochronosis (as the tissue looks

ochre Ochre ( ; , ), or ocher in American English, is a natural clay earth pigment, a mixture of ferric oxide and varying amounts of clay and sand. It ranges in colour from yellow to deep orange or brown. It is also the name of the colours produced ...

); ochronotic tissue is stiffened and unusually brittle, impairing its normal function and causing damage.

Diagnosis

If the diagnosis of alkaptonuria is suspected, it can be confirmed or excluded by collecting urine for 24 hours and determining the amount of homogentisic acid by means of

chromatography In chemical analysis, chromatography is a laboratory technique for the separation of a mixture into its components. The mixture is dissolved in a fluid solvent (gas or liquid) called the ''mobile phase'', which carries it through a system ( ...

. No assay of HGA in blood has been validated. The Genetic Testing Registry is used for maintaining information about the genetic test for alkaptonuria. The severity of the symptoms and response to treatment can be quantified through a validated questionnaire titled the AKU Severity Score Index. This assigns scores to the presence of particular symptoms and features, such as the presence of eye and skin pigmentation, joint pain, heart problems, and organ stones.

Treatment

No treatment modality has been unequivocally demonstrated to reduce the complications of alkaptonuria. Main treatment attempts have focused on preventing ochronosis through the reduction of accumulating homogentisic acid. Such commonly recommended treatments include large doses of

ascorbic acid Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) ...

(vitamin C) or dietary restriction of amino acids phenylalanine and tyrosine. However, vitamin C treatment does not have definitively proven effectiveness and protein restriction (which can be difficult to adhere to) has not shown to be effective in clinical studies. Several studies have suggested that the herbicide

may be effective in the treatment of alkaptonuria. Nitisinone inhibits the enzyme 4-hydroxyphenylpyruvate dioxygenase, responsible for converting tyrosine to homogentisic acid, thereby blocking the production and accumulation of HGA. Nitisinone has been used for some time at much higher doses in the treatment of

type I tyrosinemia Tyrosinemia type I is a genetic disorder that disrupts the metabolism of the amino acid tyrosine, resulting in damage primarily to the liver along with the kidneys and peripheral nerves. The inability of cells to process tyrosine can lead to chro ...

. Nitisinone treatment has been shown to cause a larger than 95% reduction in plasma and urinary HGA. The main drawback is accumulation of tyrosine, the long-term risks of which are unknown; a particular concern exists about damage to the

cornea The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical ...

of the eye. Long-term use requires frequent monitoring for complications.

Prognosis

Alkaptonuria does not appear to affect life expectancy, although the latest study on the topic is from 1985. The main impact is on quality of life; many people with alkaptonuria have disabling symptoms such as pain, poor sleep, and breathing symptoms. These generally start in the fourth decade. The typical age at requiring joint replacement surgery is 50–55 years.

Epidemiology

In most ethnic groups, the prevalence of alkaptonuria is between 1:100,000 and 1:250,000. In Slovakia and the Dominican Republic, the disease is much more common, with prevalence estimated at 1:19,000 people. As for Slovakia, this is not the result of a single mutation, but due to a group of 12 mutations in specific "hot spots" of the ''HGD'' gene. The Slovakian clustering probably arose in a small area in the northwest of the country and spread after the 1950s due to migration.

History

Alkaptonuria was one of the four diseases described by Archibald Edward Garrod, as being the result of the accumulation of intermediates due to metabolic deficiencies. He linked

with the accumulation of alkaptans in 1902, and his views on the subject, including its mode of heritance, were summarized in a 1908 Croonian Lecture at the

Royal College of Physicians The Royal College of Physicians (RCP) is a British professional membership body dedicated to improving the practice of medicine, chiefly through the accreditation of physicians by examination. Founded by royal charter from King Henry VIII in 1 ...

. The genetics of it was also studied by

William Bateson William Bateson (8 August 1861 – 8 February 1926) was an English biologist who was the first person to use the term genetics to describe the study of heredity, and the chief populariser of the ideas of Gregor Mendel following their rediscove ...

in the 1902. 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 A mummy is a dead human or an animal whose soft tissues and organs have been preserved by either intentional or accidental exposure to chemicals, extreme cold, very low humidity, or lack of air, so that the recovered body does not decay fu ...

had probably suffered from alkaptonuria.

Research directions

Research collaborations by several national centres have been established to find a more definitive treatment for alkaptonuria. This has included studies on the use of nitisinone and investigations into antioxidants to inhibit ochronosis. The ideal treatment would replace HGD enzyme function without accumulating other substances.

References

External links

{{Amino acid metabolic pathology Amino acid metabolism disorders Autosomal recessive disorders Skin conditions resulting from errors in metabolism