What is alkaptonuria and ochronosis?
Learn more Alkaptonuria is an inherited condition that causes urine to turn black when exposed to air. Ochronosis, a buildup of dark pigment in connective tissues such as cartilage and skin, is also characteristic of the disorder. This blue-black pigmentation usually appears after age 30.
What gene mutation causes alkaptonuria?
Mutations in the HGD gene cause alkaptonuria. Alkaptonuria is a genetic disorder, and urine that turns dark is present from birth. However, additional symptoms usually do not appear until adulthood.
What are the symptoms of alkaptonuria?
Alkaptonuria is a genetic disorder, and urine that turns dark is present from birth. However, additional symptoms usually do not appear until adulthood. Symptoms are generally slowly progressive. The urine of individuals with alkaptonuria may be abnormally dark or it may turn black upon long-standing exposure to the air.
Should alkaptonuria be suspected in individuals with osteoarthritis?
Alkaptonuria should be suspected in individuals with dark urine. However, since some individuals with alkaptonuria do not have dark urine, it may be advisable to rule out the disorder for all individuals with osteoarthritis, especially those with an early onset of symptoms.
What is the inheritance pattern of alkaptonuria?
Inheritance. This condition is inherited in an autosomal recessive pattern , which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
What are some effective treatments for alkaptonuria?
Alkaptonuria is a lifelong condition – there's currently no specific treatment or cure. However, a medicine called nitisinone has shown some promise, and painkillers and lifestyle changes may help you cope with the symptoms.
Is alkaptonuria a inherited disorder?
Alkaptonuria is inherited as an autosomal recessive trait. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent.
Who showed that alkaptonuria is caused by an inherited recessive gene?
In 1902, British physician Archibald Garrod, on the advice of his colleague, Bateson, demonstrated that alkaptonuria is inherited according to Mendelian rules and involves a rare recessive mutation. It was among the first conditions ascribed to a genetic cause. But the gene involved remained unknown until the 1990s.
Why is my urine turning black?
Urine naturally has some yellow pigments called urobilin or urochrome. The darker urine is, the more concentrated it tends to be. Dark urine is most commonly due to dehydration. However, it may be an indicator that excess, unusual, or potentially dangerous waste products are circulating in the body.
How does vitamin C help in alkaptonuria?
Ascorbic acid (ASC), more commonly known as vitamin C, is an antioxidant believed to reduce the conversion of HGA to BQA via oxidation. However, investigation revealed that although ASC reduced the HGA to BQA conversion, it did not affect HGA urinary excretion.
How are inborn errors of metabolism treated?
The management of inborn errors of metabolism has traditionally consisted in diet therapy and supportive therapy, but recently other treatment options have become available, including enzyme and coenzyme replacement, removal of harmful substances, cell and organ transplantation, and gene therapy.
Who first diagnosed alkaptonuria?
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.
Why Benedict test is positive in alkaptonuria?
Reducing sugar, Ascorbic acid, High level of uric acid or glucuronide may give Benedict's test positive. Result should be counter checked with Uristrip / Dipstrip for Glucose. Alkaptonuria gives Uristrip test negative.
What is the cause of alkaptonuria?
Causes. Alkaptonuria is caused by mutation of the homogentisate 1,2-dioxygenase ( HGD) gene. The HGD gene contains instructions for creating (encoding) an enzyme known as homogentisate 1,2-dioxygenase. This enzyme is essential for the breakdown of homogentisic acid.
What causes the whites of the eyes to turn discolored?
In some cases, the whites of the eyes (sclera) may also become discolored. In adulthood, affected individuals also develop progressive arthritis of the spine and large joints. The HGD gene codes for the enzyme required for the breakdown of homogentisic acid. Mutations in the HGD gene cause alkaptonuria.
What is the genetic condition of alkaptonuria?
Alkaptonuria is a rare genetic metabolic disorder characterized by the accumulation of homogentisic acid in the body. Affected individuals lack enough functional levels of an enzyme required to breakdown homogentisic acid. Affected individuals may have dark urine or urine that turns black when exposed to air. However, this change may not occur for several hours after urination and often goes unnoticed. Aside from dark urine that is present from infancy, affected individuals generally do not develop symptoms (asymptomatic) during infancy or childhood and often remain unaware of their condition until adulthood. Affected individuals eventually develop ochronosis, which is the bluish-black discoloration of connective and other tissue within the body. Affected individuals may develop discoloration of the skin overlying cartilage within the body such as over part of the outer ear. In some cases, the whites of the eyes (sclera) may also become discolored. In adulthood, affected individuals also develop progressive arthritis of the spine and large joints. The HGD gene codes for the enzyme required for the breakdown of homogentisic acid. Mutations in the HGD gene cause alkaptonuria.
How do you know if you have alkaptonuria?
The first noticeable signs and symptoms of alkaptonuria usually do not develop until approximately 30 years of age and are due to chronic accumulation of homogentisic acid in connective tissue, especially cartilage. Affected individuals develop a condition called ochronosis, in which connective tissue such as cartilage turns blue, grey or black due to the chronic accumulation of homogentisic acid. In many individuals, cartilage within the ear may become thickened, irregular and discolored blue, grey or black. Eventually, this discoloration may be apparent on the skin overlying the cartilage. In many cases, the whites of the eyes (sclera) also become discolored. However, this pigmentation does not interfere with vision.
Why is vitamin C used for alkaptonuria?
In older children and adults, high-doses of vitamin C have also been used to treat alkaptonuria because it hinders the accumulation and deposition of homogentisic acid. However, long-term use of vitamin C has generally proven ineffective and definite clinical studies on its efficacy are lacking.
How old do you have to be to have alkaptonuria surgery?
Approximately half of individuals with alkaptonuria will require hip, knee or shoulder joint replacement, often by 50-60 years of age. Infrequently, individuals require spinal surgery, including fusion and/or removal of the lumber discs.
How many people have alkaptonuria?
Alkaptonuria affects males and females in equal numbers, although symptoms tend to develop sooner and become more severe in males. More than 1,000 affected individuals have been reported in the medical literature. The exact incidence of alkaptonuria is unknown.
What causes alkaptonuria?
Mutations in the HGD gene cause alkaptonuria. The HGD gene provides instructions for making an enzyme called homogentisate oxidase. This enzyme helps break down the amino acids phenylalanine and tyrosine, which are important building blocks of proteins. Mutations in the HGD gene impair the enzyme's role in this process. As a result, a substance called homogentisic acid, which is produced as phenylalanine and tyrosine are broken down, accumulates in the body. Excess homogentisic acid and related compounds are deposited in connective tissues, which causes cartilage and skin to darken. Over time, a buildup of this substance in the joints leads to arthritis. Homogentisic acid is also excreted in urine, making the urine turn dark when exposed to air.
Why does my urine turn black?
Alkaptonuria is an inherited condition that causes urine to turn black when exposed to air. Ochronosis, a buildup of dark pigment in connective tissues such as cartilage and skin, is also characteristic of the disorder. This blue-black pigmentation usually appears after age 30.
What is the substance that is produced as phenylalanine and tyrosine?
As a result, a substance called homogentisic acid, which is produced as phenylalanine and tyrosine are broken down, accumulates in the body. Excess homogentisic acid and related compounds are deposited in connective tissues, which causes cartilage and skin to darken.
When does alkaptonuria appear?
This blue-black pigmentation usually appears after age 30. People with alkaptonuria typically develop arthritis, particularly in the spine and large joints, beginning in early adulthood. Other features of this condition can include heart problems, kidney stones, and prostate stones.
How many people have alkaptonuria?
This condition is rare, affecting 1 in 250,000 to 1 million people worldwide. Alkaptonuria is more common in certain areas of Slovakia (where it has an incidence of about 1 in 19,000 people) and in the Dominican Republic.
What is inherited gene?
Inheritance. This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
What is the name of the enzyme that breaks down a toxic substance?
Alkaptonuria is a rare inherited disorder. It occurs when your body can’t produce enough of an enzyme called homogentisic dioxygenase (HGD). This enzyme is used to break down a toxic substance called homogentisic acid.
Why does my urine turn dark brown?
This typically leads to osteoarthritis, especially in your spine and large joints. People with alkaptonuria also have urine that turns dark brown or black when it’s exposed to air.
What test can be used to test for homogentisic acid in urine?
They may also test you for the condition if you develop early onset osteoarthritis. Your doctor can use a test called gas chromatography to look for traces of homogentisic acid in your urine. They can also use DNA testing to check for the mutated HGD gene. Family history is very useful in making a diagnosis of alkaptonuria.
What is the best treatment for alkaptonuria?
As a result those with alkaptonuria may need a shoulder, knee, or hip replacement. You may also require surgery to replace your aortic or mitral heart valves, if they stop working properly. In some cases, you may need surgery or other therapies to treat chronic kidney or prostate stones.
What are the risks of a syringe?
However, the disease puts you at much higher risk of certain disorders, including: arthritis in your spine, hips, shoulders, and knees. tearing of your Achilles tendon. hardening of your heart’s aortic and mitral valves. hardening of your coronary arteries.
What tests are done to check for aortic valves?
Tests to monitor the progress of your condition might include: spinal X-rays to check for disk degeneration and calcification in your lumbar spine. chest X-rays to monitor your aortic and mitral heart valves. CT (computed tomography) scans to find signs of coronary artery disease.
How many people are affected by alkaptonuria?
Alkaptonuria is a rare disease. According to the National Institutes of Health, the condition affects about 1 in 250,000 to 1 million people worldwide, but is more common in Slovakia and the Dominican Republic, affecting about 1 in 19,000 people.
How many copies of a gene do you have to inherit to be a carrier?
A person must inherit two copies of a abnormal gene, one from each parent, in order to be affected by the condition (25% chance). If a person inherits only one abnormal gene then they will be a carrier (50% chance). These outcomes occur randomly. They remain the same in every pregnancy and are the same for boys and girls.
What causes alkaptonuria?
Mutations in the homogentisate 1,2-dioxygenase (HGD) gene cause alkaptonuria. The HGD (homogentisate 1,2-dioxygenase) gene provides instructions for making an enzyme called homogentisate 1,2-dioxygenase. This enzyme helps break down the amino acids phenylalanine and tyrosine, which are important building blocks of proteins. Mutations in the HGD gene impair the enzyme’s role in this process. As a result, a substance called homogentisic acid, which is produced as phenylalanine and tyrosine are broken down, accumulates in the body. Excess homogentisic acid and related compounds are deposited in connective tissues, which causes cartilage and skin to darken. Over time, a buildup of this substance in the joints leads to arthritis. Homogentisic acid is also excreted in urine, making the urine turn dark when exposed to air.
Can alkaptonuria be detected in urine?
Alkaptonuria should be suspected in individuals with dark urine. However, since some individuals with alkaptonuria do not have dark urine, it may be advisable to rule out the disorder for all individuals with osteoarthritis, especially those with an early onset of symptoms. The diagnosis of alkaptonuria is based on the detection of a significant amount of homogentisic acid (HGA) in the urine by gas chromatography-mass spectrometry analysis. A normal 24-hour urine sample contains 20-30 mg of homogentisic acid (HGA). The amount of homogentisic acid (HGA) excreted per day in individuals with alkaptonuria is usually between one and eight grams (1000 to 8000 mg). Identification of biallelic pathogenic variants in HGD on molecular genetic testing confirms the diagnosis and allows family studies. However, this testing is not required to confirm the diagnosis.
Can alkaptonuria turn urine black?
The urine of individuals with alkaptonuria may be abnormally dark or it may turn black upon long-standing exposure to the air. However, since this change often takes several hours, it often goes unnoticed. During infancy, diapers may be stained black (from urine exposure to air), although this is often missed or ignored.
Is alkaptonuria inherited?
Alkaptonuria is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
How much HGA is in urine?
The amount of HGA excreted in the urine per day in individuals with alkaptonuria is usually between one and eight grams; a control 24-hour urine sample contains 20-30 mg of HGA. (Note: Elevated HGA can also be detected on a random urine sample.)
What causes dark urine?
Alkaptonuria is caused by deficiency of homogentisate 1,2-dioxygenase, an enzyme that converts homogentisic acid (HGA) to maleylacetoacetic acid in the tyrosine degradation pathway. The three major features of alkaptonuria are dark urine or urine that turns dark on standing, ochronosis (bluish-black pigmentation in connective tissue), and arthritis of the spine and larger joints. Ochronosis generally occurs after age 30 years; arthritis often begins in the third decade. Other manifestations can include pigment in the sclera, ear cartilage, and skin of the hands; aortic or mitral valve calcification or regurgitation and occasionally aortic dilatation; renal stones; prostate stones; and hypothyroidism.
How much HGA is in a probandis?
The biochemical diagnosis of alkaptonuria in a probandis based on the detection of a significant amount of HGA in the urine (usually 1 to 8 grams per day).
When is alkaptonuria diagnosed?
Note: In some individuals, the diagnosis of alkaptonuria is identified only after the individual seeks medical attention for chronic joint pain or after black articular cartilage is noted during orthopedic surgery.
Why is it appropriate to evaluate apparently asymptomatic older and younger sibs of an affected individual?
Evaluation of relatives at risk:It is appropriate to evaluate apparently asymptomatic older and younger sibs of an affected individual in order to identify as early as possible those who would benefit from preventive measures to help preserve overall joint mobility and function.
Does alkaptonuria affect renal function?
Renal function is critical for individuals with alkaptonuria as the kidney actively secretes HGA. Kidney injury, either acute or chronic, may impair the elimination of HGA and cause HGA to accumulate in the blood and tissues. This may lead to acidosis, hemolysis, and methemoglobinemia, which may be fatal [Davison et al 2016, Freeman & Wills 2018, Hugar et al 2019].
Is alkaptonuria ochronotic arthritis?
Ochronotic arthritis is a regular manifestation of longstanding alkaptonuria. Involvement of the spine usually appears in the third decade. In one large series, low back pain was observed prior to age 30 years in 49% of individuals and prior to age 40 years in 94% [Phornphutkul et al 2002].
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- Treatment The treatment of alkaptonuria is aimed at the specific symptoms that are present in each individual. Individuals with alkaptonuria often receive anti-inflammatory medications to treat joint pain. In severe cases, stronger medications such as narcotics may be recommended. Pain management is tailored to each individuals specific case and re...
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