Abstract
Background Alkaptonuria is a rare metabolic disorder, an autosomal recessive disease caused by the deficiency of an enzyme, homogentisate 1,2-dioxygenase. As a consequence, there is an accumulation of homogentisic acid, which deposits in connective tissues, leading to ochronotic arthropathy.
Case Presentation In this case, a 35-year-old man who was diagnosed as having alkaptonuria in 2023 at the National Institutes of Health, underwent urine analysis that showed a peak homogentisic acid level of 3383 mmol/mol creatinine. He reported that 20 days prior to admission, he woke up at night due to sudden and intense cervical pain (visual analog scale 10), with shock-like pain radiating to the lateral sides of the arms and dorsoradial areas of the forearms, which was associated with weakness in elbow flexion and signs of pyramidal release. He underwent magnetic resonance imaging of the cervical spine, which revealed an acute extruded C5 to C6 disc herniation. He subsequently underwent a C5 to C6 discectomy and anterior arthrodesis, where an ochronotic-pigmented disc was observed intraoperatively. On the first postoperative day, an improvement in elbow flexion strength was noted, and he was discharged 5 days later.
Discussion There is currently no effective and proven treatment for alkaptonuria; nitisinone has shown potential as the first effective treatment but may lead to corneal issues due to triggered tyrosinemia. The treatment for ochronotic arthropathy is primarily symptomatic, with surgical procedures reserved for more advanced degenerative cases.
Conclusion This study aims to enhance understanding of the pathophysiology of the spinal column in alkaptonuria and to explore the best surgical therapy strategies for this disease.
Alkaptonuria is a rare metabolic disorder that has an estimated incidence of 1 in 250,000 to 1 in 100,000 live births and is more prevalent in certain locations such as Slovakia and the Dominican Republic.1,2 It is an autosomal recessive disease caused by the deficiency of an enzyme, homogentisate 1,2-dioxygenase (HGD), which is involved in the catabolic pathway of aromatic rings of the amino acids phenylalanine and tyrosine. As a consequence, there is an accumulation of homogentisic acid (HGA) due to decreased conversion to 4-maleylacetoacetate.3 This acid is eliminated through our urine, and after oxidation of the acid in the external environment, it leads to the characteristic dark urine.4 With advancing age and decreased renal clearance, HGA begins to accumulate in our tissues, generating an inflammatory response and depositing primarily in our joint/cartilaginous processes, such as menisci and ligaments, causing pigmentation and joint destruction (ochronosis).1
The disease progresses slowly, usually after the third decade of life, initially presenting only with dark urine, evolving to ochronotic arthropathy (the acid deposits in chondrocytes and the cartilage matrix, causing degeneration and tissue pigmentation). Spondyloarthropathy in the thoracolumbar spine is one of the main symptoms of ochronotic arthropathy, followed by joints such as the knee, shoulder, and hip.5,6 Unfortunately, there is still no effective and proven treatment for alkaptonuria, with management restricted to symptomatic treatment similar to other arthropathies and surgical cases confined to more severe degenerative processes.7
Cervical spine involvement, such as cervical spondylotic myelopathy and acute cervical disc herniation, is rarer. The objective of this study was to describe a patient with a diagnosis of alkaptonuria who presented with signs of pyramidal release following an acute cervical disc herniation, thereby increasing knowledge about this rare disease and its significant morbidity for the musculoskeletal system.
Case Report
The patient was a 35-year-old man who reported that 20 days before admission, he experienced sudden and intense cervical pain (visual analog scale 10), with shock-like pain radiating to the lateral sides of the arms and dorsoradial areas of the forearms. He experienced relief from the pain with analgesics and Pilates 2 days into the episode and maintained mild pain since then (visual analog scale 3). The pain worsened when standing or sitting for more than 20 minutes, and the patient had complete relief when lying down or resting his head.
Regarding relevant personal history, the patient had alkaptonuria, which had been diagnosed in 2023 at the National Institutes of Health. The diagnosis was made through urine analysis, which showed a peak HGA level of 3383 mmol/mol creatinine (with a baseline value of up to 11 mmol/mol creatinine). He also had a sudden L5 to S1 disc herniation in 2022 and underwent anterior lumbar interbody fusion that same year.
Upon admission examination, the patient exhibited mild cervical pain during rotation, with muscle strength graded as 4 in elbow flexion and no other deficits in strength or sensation. The Hoffmann sign was present on the right side.
Investigation with magnetic resonance imaging of the cervical spine (Figures 1 and 2) revealed degenerative disc disease at C4 to C5 and a large extruded C5 to C6 disc herniation with spinal cord compression.
Magnetic resonance imaging of the cervical spine showing a large extruded disc herniation at the C5-C6 level (Figure 1A), with central spinal canal and spinal cord compression (Figure 1B).
Computed tomography of the cervical spine, also showing the disc herniation at the C5-C6 level, with no ligament calcifications identified (Figures 2A and 2B).
The patient underwent C5 to C6 discectomy and anterior arthrodesis (Supplemental Video 1), where an intervertebral disc with ochronotic pigmentation was observed intraoperatively (Figure 3). The procedure was completed without complications. On the first day postoperatively, an improvement in elbow flexion strength was already noted. The patient had a Blake drain in place until the second postoperative day and was discharged from the hospital on the fifth postoperative day. The histopathological examination revealed elastic and cartilaginous areas, with discrete pigmented and stony areas, in addition to myxoid and hyaline degeneration of the cartilaginous matrix, with areas of devitalization and reactive proliferation of the chondrocytes.
Postoperative computed tomography of the cervical spine, with a 10-mm maximum intensity projection, showing good positioning of the cage and resolution of the extruded disc herniation.
Discussion
The incidence of alkaptonuria can vary significantly, ranging from 1 in 250,000 to 1 in 1,000,000 live births, with the highest incidence found in northwestern Slovakia, reaching up to 1 in 19,000 live births, possibly due to the high rate of consanguineous marriages in the country.8
The clinical profile of each patient diagnosed with alkaptonuria varies greatly depending on the degree of residual activity of the HGD enzyme. However, when the patient is young, some signs may be noted during a thorough physical examination, such as pigmented sclera or dark urine after oxidation in the environment. Most often, the patient is asymptomatic until developing ochronotic arthropathy, around the third or fourth decade of life. One explanation for this is the excretion of HGA by the renal tubules, which tends to decrease with age, contributing to the ochronotic pigmentation in the joints that results from the accumulation of HGA owing to the deficiency of the enzyme HGD. This substance, when in excess, oxidizes and forms a dark pigment that deposits in various tissues of the body, including cartilage, tendons, and organs, resulting in dark coloring.9
The accumulation of this pigment in the joints, especially in the intervertebral cartilages, can lead to the development of joint diseases, such as acute cervical myelopathy. In this condition, the deposition of the ochronotic pigment in the structures of the spine can cause stiffness and degeneration of the joints, resulting in compression of the spinal cord. This compression may manifest as neurological symptoms such as pain, weakness, and coordination difficulties.
Additionally, the inflammation caused by the presence of the ochronotic pigment can contribute to the degeneration of the joints, increasing the risk of injuries and compromising motor function. Thus, the relationship between ochronotic pigmentation and joint diseases, such as cervical myelopathy, highlights the importance of early recognition of alkaptonuria for the proper management of associated orthopedic and neurological complications.
Regarding ochronotic arthropathy, the spine, typically the lumbar spine, is the first musculoskeletal site to be affected (cervical spine involvement is rarer).10 The accumulation of HGA leads to oxidative stress and the formation of free radicals, contributing to an inflammatory process and degradation of the extracellular matrix, which results in cartilage degeneration and loss of elasticity. At the level of intervertebral discs, we can observe a loss of disc height and dehydration of the discs, with ligamentous bands becoming stiffer and less flexible, contributing to pain and limited movement. Certain radiographic signs that may raise suspicion include loss of disc height at multiple levels, calcification of intervertebral discs, significant osteophyte formation, and a low rate of ligamentous calcification (the latter characteristic helps differentiate it from ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis).11
In many patients, degenerative changes are incorrectly attributed to the aging degenerative process; however, the intraoperative finding of the intervertebral disc with ochronotic pigmentation can be considered pathognomonic for the disease. In suspected cases of alkaptonuria, a urine test measuring HGA should be requested (individuals without alkaptonuria excrete <11 mmol/mol creatinine).12
There is currently no effective and proven treatment for alkaptonuria. Some studies reported that using high doses of vitamin C have reduced oxidative processes, but vitamin C13 has also been proven ineffective. Dietary restrictions of phenylalanine and tyrosine have also been shown to be ineffective, as they did not decrease the production of HGA in the blood.13 The first potential effective treatment for alkaptonuria is the herbicide nitisinone; numerous studies are underway, as it is an inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase, which would convert 4-hydroxyphenylpyruvate into HGA, contributing to a significant reduction (up to 95%) in serum levels of HGA, although it may lead to tyrosinemia and ocular consequences such as corneal keratopathy. The treatment for ochronotic arthropathy is based on symptomatic management, such as analgesics and muscle relaxants, with surgical procedures restricted to more advanced degenerative cases (as described in the case).12
Conclusions
Alkaptonuria is a very rare and little-known disease despite the significant morbidity it can cause in the daily lives of patients with this genetic condition, particularly through its clinical manifestation as ochronotic arthropathy. This work provides important information for the recognition, diagnosis, and possible treatment of alkaptonuria, even though there is still no established treatment that alters the natural history of the disease.
Supplementary material
online supplementary video 1.
Footnotes
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests The authors report no conflicts of interest in this work.
- This manuscript is generously published free of charge by ISASS, the International Society for the Advancement of Spine Surgery. Copyright © 2025 ISASS. To see more or order reprints or permissions, see http://ijssurgery.com.
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