Alkaptonuria

What is Alkaptonuria?

Alkaptonuria is a very rare genetic disorder that occurs due to a shortage of a certain enzyme called homogentisate 1,2 dioxygenase (HGD). This enzyme is typically active in several parts of the body including the liver, kidney, prostate, small intestine, and colon. It helps to convert a certain substance, homogentisic acid, into other forms during the process of breaking down an amino acid called tyrosine, which is crucial for human health.

However, when the enzyme HGD doesn’t exist, homogentisic acid is produced in excess amount by the liver, which then transforms into a pigment called ochronotic pigment polymer. When this pigment starts accumulating in various parts of the body, it can cause various health issues. This condition is known as ochronosis.

Alkaptonuria was one of the first human genetic disorders understood to follow the principles of recessive inheritance – a concept in genetics that explains how some health conditions pass from parents to their children. These principles were introduced by Archibald Garrod in 1908 in his lectures. Interestingly, it’s believed that an Egyptian mummy named Harwa, dating back to 1500 BC, could have been the first recorded case of Alkaptonuria.

The term ‘alkaptonuria’ comes from an Arabic word ‘alkali.’ It was coined by Boedeker in 1859 when he observed some unusual features in a patient’s urine. In 1866, a scientist named Virchow discovered ochronosis, recognizing the pigment’s distinctive pale brownish-yellow color, similar to ochre, under a microscope.

What Causes Alkaptonuria?

Homogentisate 1,2 dioxygenase (HGD) is a protein in our body that’s found in various parts such as the kidney, liver, and small intestine. This protein helps our body process an essential nutrient called tyrosine by turning a substance named homogentisic acid (HGA) into another substance known as maleylacetoacetate. HGD contains 445 different parts known as amino acids and is located on a specific section of our 3rd chromosome.

Sometimes, a mistake or ‘mutation’ in the HGD gene can mean it doesn’t make the HGD protein properly. That leads to less HGD enzyme available, which in turn causes an accumulation of homogentisic acid (HGA).

These mutations usually occur in specific parts of our genes known as exons. The normal HGD is made up of six smaller units known as a hexamer arranged in groups of two. Each group contains an iron atom. Depending on the mutation, it can alter the function, structure, or solubility (ability to dissolve) of the HGD protein.

In rare cases, this genetic disorder can be passed down from parents to their children in what’s known as ‘autosomal dominant’ inheritance. But in certain situations, other genes may be responsible for the condition.

Risk Factors and Frequency for Alkaptonuria

Alkaptonuria is a rare disease that affects people all over the world. It’s seen in about 1 out of every 100,000 to 250,000 people globally. In the United States, it’s even rarer, affecting roughly 1 in a million people. According to certain organizations, there are 92 known cases in the U.S. The disease is most commonly reported in the Dominican Republic and Slovakia. It occurs in all racial groups but is slightly more common in individuals of African descent. Alkaptonuria affects men and women equally, though it tends to be more severe in men.

• Alkaptonuria is a rare, global disease.
• It affects 1 out of 100,000 to 250,000 people worldwide.
• In the US, it’s even rarer, impacting about 1 in a million.
• The actual number of known cases in the US is 92.
• The disease is most commonly seen in the Dominican Republic and Slovakia.
• Alkaptonuria affects all races but is slightly more common in people of African descent.
• Men and women are affected equally, but the disease is generally more severe in men.

Signs and Symptoms of Alkaptonuria

Alkaptonuria is a rare inherited disorder that often shows no signs of it being present in the family. A distinct sign of alkaptonuria, especially in children, is the darkening of urine when exposed to the air for a prolonged time. This is due to a substance called homogentisic acid reacting with the air. In certain cases, however, the urine may not darken, and this sign can therefore be unreliable. Other common symptoms are arthritis, specifically affecting the spine, hips, and knees. In fact, nearly everyone with Alkaptonuria will eventually develop arthritis. Back pain, specifically in the lower and middle back regions, often surfaces around age 30. As a person grows older, they may experience further spine-related problems including a forward-leaning posture, narrowing of the spaces within the spine, and pressure on the spinal cord.

The disease can manifest in many ways – these are often grouped into three major categories, namely ochronosis, homogenistic aciduria, and ochronotic osteoarthropathy. Ochronosis typically becomes evident in a patient’s 30s or 40s and results from a buildup of a specific organic compound in various parts of the body, including the connective tissues. Over time, ochronotic arthropathy, or joint disease, develops due to a buildup of homogentisic acid polymers in the cartilage that cushions the joints.

• General: Some individuals may develop grey pigmentation in the ear cartilage or the whites of the eyes, or have discolored skin.
• Bone and Joint: Symptoms include lower back pain, arthritis causing joint swelling, limited joint movement, compromised spine and chest mobility, and a greater likelihood of fractures due to decreased bone density.
• Respiratory: There may be decreased lung capacity and restrictive lung disease.
• Cardiac: Heart conditions such as narrowing or leaking of the aortic valve, irregular heartbeats, heart failure, and an increased risk of coronary artery disease can occur.
• Neurological: Peripheral neuropathy, ringing in the ears, double vision, and an increased risk of stroke.
• Metabolic: There is a higher incidence of kidney, gallbladder, and prostate stones.

Testing for Alkaptonuria

Doctors use a scoring system to diagnose and evaluate Alkaptonuria (AKU), a rare genetic condition that affects the body’s ability to process certain proteins. This method is known as the AKU Severity Score Index (AKUSSI). It measures the severity of the disease by assessing specific symptoms. These symptoms include:

* Changes in eye and ear color
* The presence of stones in the prostate and saliva glands
* Thinning of the bones, known as osteopenia
* Signs of stroke
* Heart problems, such as aortic valvular heart disease, heart failure, and irregular heartbeats known as atrial fibrillation

Apart from these symptoms, doctors rely on different tests and scans to diagnose AKU.

1. The primary test to diagnose alkaptonuria is the urine test for Homogentisic acid (HGA). In this test, doctors use gas chromatography-mass spectrometry (a type of chemical analysis) to measure how much HGA is present in your urine over 24 hours. Patients with AKU usually have between 1 and 8 grams of HGA in their urine each day. However, changes in urine color can be due to many reasons and aren’t enough to confirm AKU.

2. Genetic testing can pinpoint the specific changes or mutations in a gene known as HGD. This information can be useful when planning a family, especially if a genetic condition like AKU runs in the family.

3. Imaging tests such as computed tomography (CT scan) or magnetic resonance imaging (MRI) can help gauge the severity of joint problems caused by AKU.

4. Doctors may use an imaging test called a 2D-Echocardiography to spot abnormalities in the heart valves.

5. A CT Angiogram can be used to detect calcification (hardening due to calcium build-up) in the coronary vessels (the blood vessels that supply the heart).

By evaluating all these factors, doctors can form a clear picture of the severity of AKU, formulate a precise diagnosis, and plan the appropriate treatment.

Treatment Options for Alkaptonuria

Despite being one of the first genetic disorders identified as following Mendel’s laws of genetics, there is still no effective treatment for alkaptonuria, also known as AKU. The current care for AKU is aimed at controlling symptoms. This includes managing pain, physical therapy, and surgeries on the joints. The main goal of treatment is to minimize the buildup of a substance called homogentisic acid (HGA), which causes issues in the body.

One common recommendation is ascorbic acid, more commonly recognized as vitamin C. It is used because it can help slow the conversion of homogentisic acid to another compound, benzoquinone acetic acid, through a process called oxidation. However, it doesn’t lower the amount of homogentisic acid that gets excreted in the urine.

Another option considered is adopting a low protein diet. This can lower the body’s load of an amino acid called tyrosine and lessen the severity of the disease. But sticking to the dietary requirements of this approach can be challenging, and it’s unclear how effective it is.

Research has suggested that a substance called nitisinone, commonly known as a weed killer, could be significantly beneficial in treating AKU. The body uses an enzyme called 4-hydroxyphenylpyrvute dioxygenase to convert a substance called hydroxyphenylpyruvate to homogentisic acid. Nitisinone blocks this conversion process, hence reducing the amount of homogentisic acid in the body. With a dosage of 2 mg/day, nitisinone has been shown to cause more than 95% reduction in the amount of homogentisic acid in urine and blood, therefore raising the levels of tyrosine. However, higher tyrosine levels can also lead to serious side effects such as irritation in the cornea, reduced white blood cell count (leukopenia), low platelet count (thrombocytopenia), and a type of blood disorder known as porphyria.

What else can Alkaptonuria be?

Here are some conditions that might be considered when making a diagnosis:

• Osteoarthritis
• Ochronosis
• Melanosarcoma
• Rheumatoid arthritis
• Valvular heart disease
• Acute porphyria
• Ankylosing spondylitis

What to expect with Alkaptonuria

This condition doesn’t appear to shorten a person’s life. However, it can significantly affect the quality of their life. For instance, many people who have this disease, also known as AKU, often suffer from symptoms like sleep deprivation, pain, and difficulty in breathing. These symptoms usually start to appear when they’re in their forties.

Possible Complications When Diagnosed with Alkaptonuria

• Kidney and prostate stones
• Gallbladder stones
• Salivary gland stones
• Burst tendons and ligaments
• Weak and broken bones
• Hardening and narrowing of the aortic valve
• Amyloidosis, a condition where abnormal proteins build up in organs and tissues

Preventing Alkaptonuria

It’s very important for patients to understand their health condition. Learning about their disease, how to spot symptoms, and making changes to their daily lifestyle and diet, including eating less protein, can significantly improve their long-term health. This is particularly crucial for people living with AKU (Alkaptonuria, a rare inherited genetic disorder). Sessions to educate and support patients about healthy lifestyle choices can be very beneficial.

Beyond this, it’s equally important to provide genetic counseling for all family members. This helps them understand the genetic nature of the condition and what it means for them and any potential future children.

In some cases, patients might need surgery, like knee and hip replacements. These procedures can greatly improve their quality of life by reducing pain and increasing mobility.