GeneHealth - Your precision medicine

Alkaptonuria

Disease Details

Family Health Simplified

Buy Membership

Description: Alkaptonuria is a rare genetic disorder in which the body cannot properly break down certain amino acids, leading to the buildup of homogentisic acid that can cause dark urine and damage to bones and cartilage.
Type: Alkaptonuria is a metabolic disorder. It is transmitted in an autosomal recessive pattern.
Signs And Symptoms: Patients with alkaptonuria are asymptomatic 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 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 may be affected, increasing the risk of bone fractures, and rupture of tendons and muscles may occur.Valvular heart disease, mainly calcification and regurgitation of the aortic and mitral valves, may occur, and in severe and progressive cases, valve replacement may be necessary. Irregularities in the heart rhythm and heart failure affect a significant proportion of people with alkaptonuria (40% and 10%, respectively). Hearing loss affects 40% of people. Also, a propensity to developing kidney stones exists, and eventually also gallstones and stones in the prostate and salivary glands (sialolithiasis) can occur.
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.
Onset: Alkaptonuria is typically characterized by the following:

**Onset:**
- Symptoms can present early in childhood with dark-staining urine, but more serious manifestations like ochronosis (bluish-black discoloration of connective tissues) and arthritis usually develop in adulthood, often around the fourth decade of life.

**Natural History:**
- Alkaptonuria is a lifelong condition.
- Early symptoms include dark urine.
- As individuals age, they may develop ochronosis, leading to pigmentation changes in the eyes, ears, and skin.
- In adulthood, joint pain and arthritis, especially in the spine and large joints, become prominent.
- Cardiac and renal complications can also emerge in later stages.
Prevalence: Alkaptonuria is a rare genetic disorder. Its estimated prevalence is about 1 in 250,000 to 1 in 1,000,000 people worldwide. It is more common in certain regions, such as Slovakia and the Dominican Republic.
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.
Intractability: Yes, alkaptonuria is generally considered intractable. It is a rare genetic disorder caused by a deficiency of the enzyme homogentisate 1,2-dioxygenase, which leads to the accumulation of homogentisic acid in the body. Currently, there is no cure for alkaptonuria, and treatment primarily focuses on managing symptoms and complications.
Disease Severity: Alkaptonuria is a rare genetic disorder characterized by the body's inability to properly break down two amino acids, tyrosine and phenylalanine. This leads to the buildup of a substance called homogentisic acid, which can cause various symptoms.

Disease Severity: Alkaptonuria can range from mild to severe. Symptoms often start in early adulthood and can worsen over time, leading to darkening of urine, ochronosis (bluish-black discoloration of connective tissues), and arthritis, particularly in the spine and large joints.

It is important to monitor symptoms and seek medical advice for proper management and treatment.
Healthcare Professionals: Disease Ontology ID - DOID:9270
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 (exons 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.
The HGD enzyme is involved in the metabolism (chemical processing) of the aromatic amino acids phenylalanine and tyrosine. 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 hormones (e.g. thyroxine, the thyroid hormone), melanin (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 and malate. In alkaptonuria, the HGD enzyme cannot metabolize the homogentisic acid (generated from tyrosine) into 4-maleylacetoacetate, 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 polymers that resemble the skin pigment melanin. These are deposited in the collagen, a connective tissue protein, of particular tissues such as cartilage. This process is called ochronosis (as the tissue looks ochre); ochronotic tissue is stiffened and unusually brittle, impairing its normal function and causing damage.
Carrier Status: Alkaptonuria is an autosomal recessive disorder. Individuals who carry one copy of the mutated gene (heterozygotes) are considered carriers and typically do not show symptoms. Carriers have a 25% chance of having an affected child if both parents are carriers. The condition is caused by mutations in the HGD gene.
Mechanism: Alkaptonuria is a rare genetic disorder characterized by the accumulation of homogentisic acid in the body. This buildup is due to a deficiency in the enzyme homogentisate 1,2-dioxygenase (HGD), which is responsible for breaking down homogentisic acid during the catabolism of tyrosine and phenylalanine.

**Mechanism:**
- **Deficiency in HGD enzyme:** The mutation in the HGD gene leads to reduced or absent activity of the HGD enzyme.
- **Accumulation of homogentisic acid:** Because the enzyme is deficient, homogentisic acid is not properly metabolized and accumulates in various body tissues, including cartilage, skin, and sclera.
- **Excretion and pigmentation:** The excess homogentisic acid is excreted in the urine. Upon exposure to air, it oxidizes and turns the urine dark.

**Molecular Mechanisms:**
- **Genetic mutation:** The HGD gene is located on chromosome 3q21-q23. Mutations in the HGD gene are inherited in an autosomal recessive manner, meaning an individual needs two defective copies (one from each parent) to exhibit symptoms of alkaptonuria.
- **Types of mutations:** Various types of mutations in the HGD gene, such as missense, nonsense, and splice-site mutations, can disrupt the enzyme's function. These mutations can lead to improper folding or instability of the HGD enzyme.
- **Pathway disruption:** The disruption in the tyrosine degradation pathway prevents the conversion of homogentisic acid to maleylacetoacetic acid, leading to its accumulation and subsequent conversion into pigmented polymers that deposit in connective tissues.

Understanding these molecular mechanisms is crucial for developing potential therapeutic strategies, such as enzyme replacement therapy or gene-targeted therapies, to manage or treat alkaptonuria.
Treatment: In 2012 the AKU Society formed a consortium called DevelopAKUre to prove that nitisinone, a drug already approved for treating another rare disease, hereditary tyrosinaemia type-1, could be repurposed to treat AKU.
The DevelopAKUre trials concluded in 2019 and successfully illustrated that nitisinone lowered levels of homogentisic acid (HGA), the acid that causes the damage in AKU, by 99% which effectively halts the progression of the disease. In 2020, the European Medicines Agency and the European Commission approved the use of nitisinone for treating AKU making the treatment available to patients across the Europe and the UK.
Nitisinone has revolutionised the treatment of AKU, however it can lead to a condition known as hypertyrosinaemia caused by elevated levels of the amino acid tyrosine. Hypertyrosinaemia can lead to serious symptoms including corneal keratopathy, dermal toxicity, neurodevelopment delay issues in children, and alterations of wider metabolism. There is currently no effective treatment for hypertyrosinaemia other than limiting protein intake. Due to the potential side-effects of nitisinone treatment it is currently only prescribed to children aged 16 and above in Europe and patients will then have to follow a protein restricted diet and closely manage their tyrosine levels through frequent monitoring.
Compassionate Use Treatment: Alkaptonuria is a rare metabolic disorder characterized by the accumulation of homogentisic acid. Compassionate use treatment, off-label, or experimental treatments for alkaptonuria may include:

1. **Nitisinone (NTBC)**: Originally approved for treating tyrosinemia type 1, nitisinone has shown effectiveness in reducing homogentisic acid levels in patients with alkaptonuria. It is often used off-label for this purpose.

2. **Vitamin C**: Some studies suggest that high doses of Vitamin C might reduce the accumulation of homogentisic acid, although this is not a definitive treatment and is considered more supportive.

3. **Enzyme Replacement Therapy**: Research is ongoing into enzyme replacement therapies that could potentially break down homogentisic acid, but these remain experimental at this stage.

Clinical trials and ongoing research may provide additional options in the future. It is important for patients to discuss potential treatments with their healthcare provider to determine the best course of action.
Lifestyle Recommendations: For alkaptonuria, here are the lifestyle recommendations:

1. **Dietary modifications**: Limit intake of foods high in phenylalanine and tyrosine, such as meat, dairy products, and certain beans. This can help reduce the accumulation of homogentisic acid.

2. **Hydration**: Maintain adequate hydration to help the body flush out excess homogentisic acid.

3. **Regular exercise**: Engage in low-impact exercises to maintain joint mobility and reduce the risk of arthritis-related complications.

4. **Avoid heavy lifting and high-impact sports**: To minimize stress on the joints and spine, avoid activities that can exacerbate joint and back problems.

5. **Regular check-ups**: Schedule regular check-ups with your healthcare provider to monitor the progression of the disease and manage symptoms effectively.

6. **Joint protection strategies**: Use supportive footwear and ergonomic tools to reduce strain on joints.

Focus on maintaining a balanced lifestyle to manage symptoms and improve quality of life.
Medication: There is no specific medication to cure alkaptonuria, but treatment mainly focuses on managing symptoms. Nitisinone has shown some promise in reducing homogentisic acid levels, although its long-term efficacy and safety are still under evaluation. Additionally, vitamin C supplementation may be recommended to slow the deposition of ochronotic pigment in tissues. Regular monitoring and supportive care are crucial for managing joint and cardiac complications.
Repurposable Drugs: There are no widely recognized repurposable drugs specifically approved for the treatment of alkaptonuria. However, nitisinone (originally developed for treating hereditary tyrosinemia type 1) has shown promise in clinical trials for alkaptonuria by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase, which leads to reduced levels of homogentisic acid, the substance that accumulates in individuals with alkaptonuria.
Metabolites: Alkaptonuria is a rare genetic disorder caused by the deficiency of the enzyme homogentisate 1,2-dioxygenase. The primary metabolite that accumulates in individuals with alkaptonuria is homogentisic acid. This accumulation leads to various symptoms, including darkening of the urine when exposed to air and ochronosis, which is the bluish-black discoloration of connective tissues.
Nutraceuticals: There are no specific nutraceuticals that have been conclusively proven to treat or manage alkaptonuria. However, a low-protein diet to reduce the intake of phenylalanine and tyrosine, the amino acids involved in this condition, may be beneficial. This dietary approach aims to decrease the accumulation of homogentisic acid, which contributes to the symptoms of alkaptonuria. Always consult a healthcare provider for personalized advice and treatment plans.
Peptides: Alkaptonuria is not directly related to peptides but involves the deficiency of the enzyme homogentisate 1,2-dioxygenase, which is required to break down homogentisic acid. The buildup of this acid leads to various symptoms. The term "nan" appears to be unrelated to the context of alkaptonuria.