alkaptonuria

Alkaptonuria is a metabolic condition characterized by the buildup of homogentisic acid and its oxidized products in connective tissues, leading to discoloration of the eyes, ears, and cartilage as well as joint disease. It is caused by pathogenic variants in the HGD gene, which disrupt the normal breakdown of tyrosine. This condition affects both males and females and is considered rare, impacting approximately 1 to 9 per million people. Early manifestations often include darkening of the urine when exposed to air and subtle pigment changes in the sclera.

Individuals with alkaptonuria typically experience a range of symptoms that evolve over time. Characteristic findings include dark urine that darkens on standing and ochronosis, the grey-blue discoloration of the sclera and ear cartilage. As the condition progresses, many affected individuals develop joint swelling, stiffness, and osteoarthritis, which may lead to joint dislocation and low back pain. In addition, calcifications in cartilage, intervertebral disks, and cardiac structures, along with variable manifestations such as abnormal skin pigmentation, nephrolithiasis, and hearing or vision abnormalities, are reported. Not all individuals experience all features, and severity varies considerably.

Alkaptonuria results from pathogenic variants in the HGD gene, which encodes the enzyme homogentisate dioxygenase that is essential for the normal metabolism of tyrosine. Deficiency of this enzyme leads to the systemic accumulation of homogentisic acid, causing the pigmentary and joint changes observed in the condition. The condition is inherited in an autosomal recessive manner, meaning that an affected individual has received one mutated copy of the gene from each parent. , alkaptonuria is more common when parents share a common ancestor, as the probability that both are carriers of the same rare genetic variant is increased.

Currently, management of alkaptonuria focuses on supportive care and symptom management, as there are no FDA-approved treatments specifically for this condition. Treatment is tailored to the individual and typically involves a multidisciplinary team to address joint issues, pigmentation changes, and other complications. Regular surveillance is an essential part of long-term care, helping to identify potential complications early so that appropriate interventions can be initiated. Genetic counseling is recommended to help families understand the inheritance pattern and explore management options with their healthcare team.

The course of alkaptonuria is highly variable, with outcomes depending on the severity of symptoms, age at diagnosis, and access to specialized care. Although joint and connective tissue issues may progressively affect quality of life, many individuals manage these complications through supportive care and regular monitoring. Outcomes described in medical literature continue to evolve as standards of care improve. Families are encouraged to connect with specialists and genetic counseling services to navigate long-term management strategies and address individual concerns.

Several clinical trials are currently investigating new treatment approaches for alkaptonuria, offering hope for future therapeutic options. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.