1. Background and Importance
Homogentisate 1, 2-dioxygenase deficiency which is a rare Autosomal Recessive (AR) metabolic disorder can lead to tyrosine metabolism impairment. Alkaptonuria was first announced by Sir Archibald Garrod in 1908, with an estimated incidence of 1:250,000–1000,000 [1, 2]. Due to homogentisate 1, 2-dioxygenase deficiency, oxidized polymers of Homogentisic Acid (HGA) accumulate in connective tissues and excrete in urine. In Alkaptonuria disease, homogentisic acid deposits in different parts of body and results in multi-organ involvements. The characteristic bluish-black discoloration of the skin and cartilage tissue are known as ochronosis [3].
Spine and other large joints are usually involved in ochronosis. Spinal ankylosis especially in thoracic and lumbar segments is the result of loss of flexibility in ochronosis [4]. The onset of the symptoms in the spinal region may be mild or subtle and become acute after disc herniation. Although progressive degeneration of the intervertebral discs and spondylosis are usual presenting features, the severity of the radiological changes is not completely compatible with the symptoms. Disc prolapse is not usual in ochronosis and rarely needs surgical intervention [5-8].
In this study, we described a case of chronic low back pain in a 45-year-old female patient presenting with chronic low back and left leg radiated pain and no previous history of alkaptonuria.
2. Case presentation
A 45-year-old female patient referred to our outpatient clinic in Shahid Madani Hospital, Karaj, Iran, with chronic low back and left radiated leg pain that aggravated gradually in the previous six months. She also suffered from progressive muscle weakness in her left lower extremity. Her lower back pain had been disturbing her for about five years and was relieved by NSAIDs until the previous six months before she came. There were no other significant features in her past medical history. Neurological examination revealed a positive Straight Leg Raise (SLR) test and a diminished patellar reflex on the left extremity. Motor strength of the dorsiflexor muscles was moderately weak, and there was hypoaesthesia along with the L3 and L4 dermatomes on the left side in physical examination. 
The radiographic studies revealed significant degenerative changes and disc space narrowing with sclerosis of endplates (Figures 1 and 2). Lumbosacral magnetic resonance imaging (MRI) revealed degenerative changes, disc space narrowing and disc herniation at the level L3-L4 (Figure 3). The patient was operated, and L3-L4 discectomy was done. Macroscopically, no abnormality of the skin, muscles or ligaments was observed during surgery. After incision of the annulus in level L3-L4, surprisingly the excised nucleus pulposus tissue was black (Figure 4). The microscopic histologic examination revealed melanin-like deposition in the chondrocytes cytoplasm of the degenerated disc material (Figure 5). 
Afterwards, the patient was re-examined for possible diagnosis of alkaptonuria, but there was no obvious color change in sclera, cornea, and skin. Furthermore, the patient did not mention any discoloration of urine or any stain on her underwear, and there was no family history. After detection of homogentisic acid in the urine, the diagnosis was confirmed by thin-layer chromatography. The postoperative course was uneventful, and she was free from low back and leg pain after surgery. She was discharged with oral ascorbic acid (1000 mg per day) treatment and dietary restrictions. Six months after surgery, the patient did recover full motor and sensory functions, and only complained of mild back pain.
3. Discussion
Ochronosis is the accumulation of homogentisic acid in tissues leading to dark bluish pigmentation of connective tissues including the joints, eyes, skin, and cardiovascular and genitourinary systems. Auricular cartilage is commonly involved [9]. The most common manifestation of alkaptonuria is ochronotic arthropathy [1, 5, 9, 10], which affects large weight-bearing joints and typically manifests in the third or fourth decade of life. The lumbar spine is affected initially and will often present with low back pain and stiffness with limited lumbar range of motion [6, 11, 12]. 
The main cause of symptoms manifestation after middle age is the reduction of renal clearance of homogenistic acid by aging. In most of symptomatic cases, the first physical signs of ochronosis presents during the third decade of life. The usual signs are slight bluish-black or grayish-blue pigmentations of the pinnae of the ears, sclera, cornea, and conjunctiva of the eyes [3]. Arthropathy occurs in patients with alkaptonuria due to ochronosis in connective tissues, and the lumbar spine is usually involved before the other joints, but future involvement of knees, hips and shoulders is possible [13]. 
Disc spaces reduction and wafer-like calcification in radiographic studies are characteristic findings for diagnosis of ochronosis with lumbar involvement [13]. Our patient’s radiographic evaluation revealed these aforementioned findings, but it was not assumed as ochronosis until the visualization of pigmented nucleus pulposus was provided. Our patient presented with no systemic manifestations in her fourth decade. It has been reported that most of the patients do not seek medical attention until symptomatic ochronotic arthropathy occurs [14]. 
Early diagnosis and being aware of alkaptonuria are advantageous in patients as symptomatic treatment of it can be initiated. The therapeutic regimen includes a megadose of vitamin C for the degradation of HGA [15]. Evaluation of other systemic organs such as cardiovascular and urinary organs should also be done in early stages.
Ethical Considerations
Compliance with ethical guidelines
All ethical principles were considered in this article. The participants were informed about the purpose of the research and its implementation stages; they were also assured about the confidentiality of their information. Moreover, they were allowed to leave the study whenever they wish, and if desired, the results of the research would be available to them.
Funding
This study was supported by Alborz University of Medical Sciences, Karaj, Iran.
Authors' contributions
Conceptualization and methodology: Ali Baradaran Bagheri; Data collection: Farsad Biglari; Data Analysis: Salman Azarsina; Drafting the article, Critically revising the article, reviewing the submitted version of manuscript, and approving the final version of the manuscript: All authors.

Conflict of interest
The authors declared no conflicts of interests.


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