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Orphanet Journal of Rare Diseases Aug 2023Inborn metabolic diseases (IMD) are rare conditions that can be diagnosed during adulthood. Patients with IMD may have joint symptoms and the challenge is to establish... (Review)
Review
Inborn metabolic diseases (IMD) are rare conditions that can be diagnosed during adulthood. Patients with IMD may have joint symptoms and the challenge is to establish an early diagnosis in order to institute appropriate treatment and prevent irreversible damage. This review describes the joint manifestations of IMD that may be encountered in adults. The clinical settings considered were arthralgia and joint stiffness as well as arthritis. Unspecific arthralgias are often the first symptoms of hereditary hemochromatosis, chronic low back pain may reveal an intervertebral disc calcification in relation with alkaptonuria, and progressive joint stiffness may correspond to a mucopolysaccharidosis or mucolipidosis. Gaucher disease is initially revealed by painful acute attacks mimicking joint pain described as "bone crises". Some IMD may induce microcrystalline arthropathy. Beyond classical gout, there are also gouts in connection with purine metabolism disorders known as "enzymopathic gouts". Pyrophosphate arthropathy can also be part of the clinical spectrum of Gitelman syndrome or hypophosphatasia. Oxalate crystals arthritis can reveal a primary hyperoxaluria. Destructive arthritis may be indicative of Wilson's disease. Non-destructive arthritis may be seen in mevalonate kinase deficiency and familial hypercholesterolemia.
Topics: Humans; Adult; Chondrocalcinosis; Gout; Joint Diseases; Metabolism, Inborn Errors; Hepatolenticular Degeneration
PubMed: 37563694
DOI: 10.1186/s13023-023-02810-6 -
Clinical Medicine Insights. Arthritis... 2023Ankylosing spondylitis is the most common type of seronegative inflammatory spondyloarthropathy often presenting with low back or neck pain, stiffness, kyphosis and... (Review)
Review
Ankylosing spondylitis is the most common type of seronegative inflammatory spondyloarthropathy often presenting with low back or neck pain, stiffness, kyphosis and fractures that are initially missed on presentation; however, there are other spondyloarthropathies that may present similarly making it a challenge to establish the correct diagnosis. Here, we will highlight the similarities and unique features of the epidemiology, pathophysiology, presentation, radiographic findings, and management of seronegative inflammatory and metabolic spondyloarthropathies as they affect the axial skeleton and mimic ankylosing spondylitis. Seronegative inflammatory spondyloarthropathies such as psoriatic arthritis, reactive arthritis, noninflammatory spondyloarthropathies such as diffuse idiopathic skeletal hyperostosis, and ochronotic arthritis resulting from alkaptonuria can affect the axial skeleton and present with symptoms similar those of ankylosing spondylitis. These similarities can create a challenge for providers as they attempt to identify a patient's condition. However, there are characteristic radiographic findings and laboratory tests that may help in the differential diagnosis. Axial presentations of seronegative inflammatory, non-inflammatory, and metabolic spondyloarthropathies occur more often than previously thought. Identification of their associated symptoms and radiographic findings are imperative to effectively diagnose and properly manage patients with these diseases.
PubMed: 37533960
DOI: 10.1177/11795441231186822 -
Biomedicines Sep 2023Endogenous ochronosis, also known as alkaptonuria, is a rare disease known for its bluish-black discoloration of the skin, sclerae, and pinnae, as well as urine that...
Endogenous ochronosis, also known as alkaptonuria, is a rare disease known for its bluish-black discoloration of the skin, sclerae, and pinnae, as well as urine that turns black upon standing. Though rarely fatal, joint degradation is a common sequela, and many patients require multiple large joint arthroplasties throughout their lifetime. Though many aspects of the pathophysiological mechanisms of the disease have been described, questions remain, such as how the initiation of ochronotic pigmentation is prompted and the specific circumstances that make some tissues more resistant to pigmentation-related damage than others. In this report, we present the case of an 83-year-old female previously diagnosed with alkaptonuria including high-quality arthroscopic images displaying the fraying of articular cartilage. We also offer a summary of the latest literature on the pathophysiological mechanisms of the disease, including cellular-level changes observed in ochronotic chondrocytes, biochemical and mechanical alterations to the cartilaginous extracellular matrix, and patterns of pigmentation and joint degradation observed in humans and mice models. With these, we present an overview of the mechanisms of ochronotic chondropathy and joint degradation as the processes are currently understood. While alkaptonuria itself is rare, it has been termed a "fundamental disease," implying that its study and greater understanding have the potential to lead to insights in skeletal biology in general, as well as more common pathologies such as osteoarthritis and their potential treatment mechanisms.
PubMed: 37892999
DOI: 10.3390/biomedicines11102625 -
JIMD Reports Jul 2023Amongst a cohort of 88 alkaptonuria (AKU) patients attending the United Kingdom National Alkaptonuria Centre (NAC), four unrelated patients had co-existing Parkinson's...
Amongst a cohort of 88 alkaptonuria (AKU) patients attending the United Kingdom National Alkaptonuria Centre (NAC), four unrelated patients had co-existing Parkinson's disease (PD). Two of the NAC patients developed PD before receiving nitisinone (NIT) while the other two developed overt PD during NIT therapy. NIT lowers redox-active homogentisic acid (HGA) and profoundly increases tyrosine (TYR). A further unpublished case of a Dutch patient with AKU and PD on deep brain stimulation is included in this report. A Pubmed search revealed a further five AKU patients with PD, all without NIT usage. The prevalence of PD in AKU in the NAC appears to be nearly 20-times higher than in the non-AKU population ( < 0.001) even when adjusted for age. We propose that life-long exposure to redox-active HGA may account for the higher prevalence of PD in AKU. Furthermore, the appearance of PD in AKU patients during NIT therapy may be due to unmasking dopamine deficiency in susceptible individuals, as a result of the tyrosinaemia during NIT therapy inhibiting the rate-limiting brain tyrosine hydroxylase.
PubMed: 37404676
DOI: 10.1002/jmd2.12367 -
Cureus Aug 2023Alkaptonuria is a rare autosomal recessive trait. Symptomatic lumbar disc herniation warranting surgical intervention is a rare scenario in alkaptonuria and only a few...
Alkaptonuria is a rare autosomal recessive trait. Symptomatic lumbar disc herniation warranting surgical intervention is a rare scenario in alkaptonuria and only a few cases have been described in the literature. We present one such rare case of alkaptonuria in a 31-year-old female presenting with low back pain and left leg radiculopathy not relieved with conservative management. Roentgenograms of the lumbar spine revealed wafer-like disc calcifications and MRI showed a herniated disc at the L4-L5 level with deeply hypointense disc spaces in T2 suggestive of disc calcification and associated modic type 2 changes. During the surgery, the disc material removed was black in color, which raised a clinical suspicion of alkaptonuria. Postoperatively, the patient was re-examined and urine homogentisic acid was found to be raised. This, along with a histopathological examination, was diagnostic of alkaptonuria. The patient had excellent relief of symptoms postoperatively. In conclusion, if a 'black disc' is found during surgery, retrospective analysis and re-examination of patient clinical features and urine examination have to be done to diagnose alkaptonuria. While making a differential diagnosis of degenerative disc disease in patients with a calcified disc seen on radiography, a high index of suspicion for alkaptonuria has to be maintained.
PubMed: 37786570
DOI: 10.7759/cureus.44395 -
International Journal of Molecular... Jul 2023Nitisinone has been approved for treatment of alkaptonuria (AKU). Non-invasive biomarkers of joint tissue remodelling could aid in understanding the molecular changes in... (Randomized Controlled Trial)
Randomized Controlled Trial
Nitisinone has been approved for treatment of alkaptonuria (AKU). Non-invasive biomarkers of joint tissue remodelling could aid in understanding the molecular changes in AKU pathogenesis and how these can be affected by treatment. Serological and urinary biomarkers of type I collagen and II collagen in AKU were investigated in patients enrolled in the randomized SONIA 2 (NCT01916382) clinical study at baseline and yearly until the end of the study (Year 4). The trajectories of the biomarkers over time were observed. After treatment with nitisinone, the biomarkers of type I collagen remodelling increased at Year 1 (19% and 40% increase in CTX-I and PRO-C1, respectively), which was potentially reflected in the higher degree of mobility seen following treatment. The biomarkers of type II collagen remodelling decreased over time in the nitisinone group: C2M showed a 9.7% decline at Year 1, and levels then remained stable over the following visits; CTX-II showed a 26% decline at Year 3 and 4 in the nitisinone-treated patients. Nitisinone treatment induced changes in biomarkers of bone and cartilage remodelling. These biomarkers can aid patient management and deepen our knowledge of the molecular mechanisms of this rare disease.
Topics: Humans; Alkaptonuria; Biomarkers; Cartilage; Collagen Type I
PubMed: 37446173
DOI: 10.3390/ijms241310996