What is alkaptonuria?
Alkaptonuria is an inherited condition that causes urine to turn 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- 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 common is 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 genes are related to 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.
How do people inherit alkaptonuria?
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 the symptoms for 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 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 (from urine exposure to air), although this is often missed or ignored.
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 due to the chronic accumulation of homogentisic acid. In many individuals, cartilage within the ear may become thickened, irregular and discolored blue, grey or . 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.
In addition to cartilage, homogentisic acid accumulates in other connective tissue including tendons and ligaments and even bone. Over time, affected tissue becomes discolored, brittle and weak. Affected individuals may develop abnormalities affecting the tendons including thickened Achilles tendons and inflammation of the tendons (tendonitis). Affected tendons and ligaments may be particularly susceptible to rupturing. Eventually, discoloration of tendons may become visible on the overlying skin.
Long-standing alkaptonuria leads to chronic joint pain and inflammation (arthritis), especially in the spine and large joints (ochronotic arthropathy). Arthritis can be severe and disabling. Low back pain and stiffness are common symptoms and are sometimes seen before the age of 30. Discs between the vertebrae flatten and calcify. Eventually, vertebrae or other bones may fuse causing stiffening or immobility of affected joints (ankylosis). Spinal involvement may lead to abnormal outward curvature of the spine causing hunching of the back (kyphosis) and loss of height. The hip, knees and shoulders are commonly affected as well. Joint mobility is usually diminished and fluid buildup in affected joints (effusions) may also occur. Joint abnormalities are progressive and may eventually necessitate a joint replacement. Joint disease in alkaptonuria tends to begin earlier and progress more rapidly in males than females.
Less often, additional symptoms may occur in alkaptonuria. Although these symptoms occur less often than the main symptoms of alkaptonuria, they occur with greater frequency than would be expected in the general population. Such symptoms include kidney stones, which develop in 50 percent of affected individuals over 64 years of age. Men with alkaptonuria may also develop prostate stones. Passage of these stones can be extremely painful.
In some individuals, heart disease may develop due to the accumulation of homogentisic acid within the aortic or mitral valves. This accumulation causes thickening of the valves and narrowing (stenosis) of the openings of the valves. Occasionally, the narrowing is severe enough that the aortic valve needs to be replaced. The aortic valve connects the lower left chamber (main pumping chamber) of the heart with the aorta (the main artery of the body). The mitral valve is located between the left upper and left lower chambers of the heart. Affected individuals may develop calcification of the valves and/or backflow of blood back through the affected valves (regurgitation), which can lead to reduced blood flow throughout the body. Widening (dilation) of the aorta may also occur. In some cases, calcification of the small blood vessels that supply blood and oxygen to the heart (coronary blood vessels) may also occur.
Alkaptonuria does not cause developmental delays or cognitive impairment and does not appear to affect life span. However, chronic pain and mobility issues can develop.
What are the causes for alkaptonuria?
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. Mutations of the HGD gene result in deficient levels of functional homogentisate 1,2-dioxygenase, which, in turn, leads to excess levels of homogentisic acid. Although homogentisic acid is rapidly cleared from the body by the kidneys, it also slowly accumulates in the various tissues of the body, especially connective tissue such as cartilage. Over time (rarely before adulthood), it eventually changes the color of affected tissue to a slate blue or . Long-term, chronic accumulation of homogentisic acid eventually weakens and damages affected tissue and leads to many of the characteristic symptoms of alkaptonuria.
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. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
What are the treatments for alkaptonuria?
There’s no specific treatment for alkaptonuria. Instead, treatment is focused largely on managing symptoms.
There are many therapies that have been tried, but unfortunately, they haven’t been proven to be effective and may be harmful or unhelpful in the long term.
However, The National Institutes of Health warns that long-term use of vitamin C can sometimes increase the production of kidney stones and has generally proven ineffective for long-term treatment of this condition.
Other treatments for alkaptonuria are focused on preventing and relieving possible complications, such as:
- heart disease
- kidney stones
For example, your doctor may prescribe anti-inflammatory medications or narcotics for joint pain. Physical and occupational therapy may help you maintain flexibility and strength in your muscles and joints.
You should also avoid activities that put a lot of strain on your joints, such as heavy manual labor and contact sports. At some point in your life, you might need surgery.
The World Institutes of Health reports adults can experience a buildup of homogentisic acid in cartilage, resulting in arthritis. 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 risk factors for alkaptonuria?
Women are more likely to develop agranulocytosis than men are. It can occur at any age. However, inherited forms of the condition are more often found in children, who usually pass away from this condition well before reaching adulthood. Acquired agranulocytosis occurs most frequently in older adults.
Is there a cure/medications for alkaptonuria?
Alkaptonuria, a rare genetic metabolic disorder, caused by the homogentisic acid accumulating in the body. An individual affected by Alkaptonuria lacks the ability to break down the homogentisic acid by the enzymes. In addition, individuals can have or dark urine.
- Yes, there is a process by which Alkaptonuria can be diagnosed and treated with medications.
- The individual will need to go through a detailed clinical evaluation and a variety of tests.
- In addition, the doctor might recommend a CT scan for artery calcification.
- In most cases, people ignore the color of urine as it turns after a long number of hours it is exposed to air.
- Alkaptonuria can be detected by testing the elevated or higher levels of homogentisic acid in the urine.
- Once it is detected, there are various types of therapies one can get:
- Anti-inflammatory medicines to reduce the pressure or pain in joints.
- Occupational and Physical therapy will help them in improving the flexibility of muscles.
- Surgical intervention
- The majority of people suffering from Alkaptonuria would require the replacement of the shoulder, knee, or hip.
- In addition, some people might need spinal surgery, including the removal and/or fusion of lumbar discs. In the end, pain management is adopted by the doctors keeping in mind the specific requirements of each customer suffering from the disease.
- Also, the diet restrictions have not benefitted people suffering from this disease, rather they can invite complications in life.
Condition that causes urine to turn when exposed to airOchronosis,Abuildup of dark pigment in connective tissues such as cartilage and skin
Lower back pain,Joint pain,Black urine,Stiffness,Etc