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William A Gahl – One of the best experts on this subject based on the ideXlab platform.

  • Aortic distensibility in Alkaptonuria.
    Molecular genetics and metabolism, 2020
    Co-Authors: Rashmi Thimmapuram, Wendy J Introne, William A Gahl, W. Patricia Bandettini, Sujata M Shanbhag, Kevin J. O’brien, Marcus Y. Chen
    Abstract:

    Abstract Introduction Alkaptonuria (AKU) is a rare inherited disorder of tyrosine metabolism resulting in an accumulation of homogentisic acid oxidation products in the joints and cardiovascular system. Aortic distensibility may be a non-invasive indicator of cardiovascular complications. Descending thoracic aortic distensibility in Alkaptonuria has not been studied. Methods Patients diagnosed with Alkaptonuria underwent Magnetic ResoResonanceging (MRI) and gated non-contrast and contrast-enhanced cardiovascular computed tomography. Using MRI cine images, aortic distensibility of the descending thoracic aortaorta was determined. Results Seventy-six patients with Alkaptonuria were imaged. When compared to literature normal values, aortic distensibility in AKU was impaired (5.2 vs 6.2 × 10−3, p  Conclusions Patients with Alkaptonuria have impaired aortic distensibility, which is likely an early marker for reduced cardiovascular health. Variables such as age, hypertension, hyperlipidemia, and aortic and coronary calcification were associated with impaired distensibility.

  • Aortic Stenosis and Vascular Calcifications in Alkaptonuria
    Molecular genetics and metabolism, 2011
    Co-Authors: Hwaida Hannoush, Wendy J Introne, William A Gahl, Marcus Y. Chen, Pim Suwannarat, Sook-jin Lee, Kevin O'brien, Michael A. Kayser, Vandana Sachdev
    Abstract:

    Alkaptonuria is a rare metabolic disorder of tyrosine catabolism in which homogentisic acid (HGA) accumulates and is deposited throughout the spine, large joints, cardiovascular system, and various tissues throughout the body. In the cardiovascular system, pigment deposition has been described in the heart valves, endocardium, pericardium, aortic intima and coronary arteries. The prevalence of cardiovascular disease in patients with Alkaptonuria varies in previous reports. We present a series of 76 consecutive adult patients with Alkaptonuria who underwent transthoracic echocardiography between 2000 and 2009. A subgroup of 40 patients enrolled in a treatment study underwent non-contrast CT scans and these were assessed for vascular calcifications. Six of the 76 patients had aortic valvvalve replacement. In the remaining 70 patients, 12 patients had aortic sclerosis and 7 patients had aortic stenstenosis. Unlike degenerative aortic valve disease, we found no correlation with standard cardiac risk factors. There was a modest association between the severity of aortic valve disease and joint involvement, however, we saw no correlation with urine HGA levels. Vascular calcifications were seen in the coronaries, cardiac valves, aortic root, descending aortaorta and iliac arteries. These findings suggest an important role for echocardiographic screening of Alkaptonuria patients to detect valvular heart disease and cardiac CT to detect coronary artery calcifications.

  • minocycline induced hyperpigmentation masquerading as Alkaptonuria in individuals with joint pain
    Arthritis & Rheumatism, 2004
    Co-Authors: Pim Suwannarat, Isa Bernardini, Chanika Phornphutkul, Maria L. Turner, William A Gahl
    Abstract:

    Alkaptonuria, a rare autosomal-recessive disorder caused by mutations in the HGD gene and a deficiency of homogentisate 1,2-dioxygenase, is characterized by accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue resulting in joint disease. Certain medications have been reported to cause cutaneous hyperpigmentation resembling that of Alkaptonuria. We present 5 such cases. Eighty-eight patients with a possible diagnosis of Alkaptonuria were examined at the National Institutes of Health Clinical Center between June 2000 and March 2004. The diagnosis of Alkaptonuria was confirmed or ruled out by measurement of HGA in the urine. Five patients with findings consistent with ochronosis, including pigmentary changes of the ear and mild degenerative disease of the spine and large joints, were diagnosed clinically as having Alkaptonuria, but the diagnosis was withdrawn based on normal urine HGA levels. All 5 patients were women who had taken minocycline for dermatologic or rheumatologic disorders for extended periods. Minocycline-induced hyperpigmentation should be considered in the differential diagnosis of ochronosis. This could be of increased significance now that minocycline and other tetracyclines have been proposed as therapeutic options for rheumatoid arthritis, bringing a new population of patients with ochronosis and arthritis to medical attention with the potential, but incorrect, diagnosis of Alkaptonuria.

Wendy J Introne – One of the best experts on this subject based on the ideXlab platform.

  • Aortic distensibility in Alkaptonuria.
    Molecular genetics and metabolism, 2020
    Co-Authors: Rashmi Thimmapuram, Wendy J Introne, William A Gahl, W. Patricia Bandettini, Sujata M Shanbhag, Kevin J. O’brien, Marcus Y. Chen
    Abstract:

    Abstract Introduction Alkaptonuria (AKU) is a rare inherited disorder of tyrosine metabolism resulting in an accumulation of homogentisic acid oxidation products in the joints and cardiovascular system. Aortic distensibility may be a non-invasive indicator of cardiovascular complications. Descending thoracic aortic distensibility in Alkaptonuria has not been studied. Methods Patients diagnosed with Alkaptonuria underwent Magnetic Resonance Imaging (MRI) and gated non-contrast and contrast-enhanced cardiovascular computed tomography. Using MRI cine images, aortic distensibility of the descending thoracic aorta was determined. Results Seventy-six patients with Alkaptonuria were imaged. When compared to literature normal values, aortic distensibility in AKU was impaired (5.2 vs 6.2 × 10−3, p  Conclusions Patients with Alkaptonuria have impaired aortic distensibility, which is likely an early marker for reduced cardiovascular health. Variables such as age, hypertension, hyperlipidemia, and aortic and coronary calcification were associated with impaired distensibility.

  • Assessment of Thyroid Function in Patients With Alkaptonuria.
    JAMA network open, 2020
    Co-Authors: Shirisha Avadhanula, Wendy J Introne, Sungyoung Auh, Steven J. Soldin, Brian R. Stolze, Debra S Regier, Carla Ciccone, Fady Hannah-shmouni, Armando C. Filie, Kenneth D. Burman
    Abstract:

    Importance Alkaptonuria is an autosomal recessive disorder caused by pathogenic variants in theHGDgene. Deficiency of the HGD enzyme leads to tissue deposition of homogentisic acid (HGA), causing severe osteoarthropathies and cardiac valve degeneration. Although HGD is vital for the catabolism of tyrosine, which provides the basis for thyroid hormhormone synthesis, the prevalence of thyroid dysfunction in Alkaptonuria is unknown. Objective To assess thyroid structure and function in patients with Alkaptonuria. Design, Setting, and Participants A single-center cohort study was conducted in a tertiary referral center including patients with Alkaptonuria followed up for a median of 93 (interquartile range, 48-150) months between February 1, 2000, and December 31, 2018. The Alkaptonuria diagnosis was based on clinical presentation and elevated urine HGA levels. A total of 130 patients were considered for participation. Main Outcomes and Measures Prevalence of thyroid dysfunction in adults with Alkaptonuria compared with the general population. Thyrotropin and free thyroxine levels were measured by immunoassay and repeated in each patient a median of 3 (interquartile range, 2-22) times. Neck ultrasonographic scans were analyzed in a subset of participants. Logistic regression was used to test the association of thyroid dysfunction with age, sex, thyroid peroxidase (TPO) antibodies, serum tyrosine levels, and urine HGA levels. Results Of the 130 patients, 5 were excluded owing to thyroidectomy as the cause of hypothyroidism. The study cohort consisted of 125 patients; the median age was 45 (interquartile range, 35-51) years. Most of the patients were men (72 [57.6%]). The prevalence of primary hyperthyroidism was 0.8% (1 of 125 patients), similar to 0.5% observed in the general population (difference, 0.003; 95% CI, −0.001 to 0.04;P = .88). The prevalence of primary hypothyroidism was 16.0% (20 of 125 patients), which is significantly higher than 3.7% reported in the general population (difference, 0.12; 95% CI, 0.10-0.24;P  Conclusions and Relevance The high prevalence of primary hypothyroidism noted in patients with Alkaptonuria in this study suggests that serial screening in this population should be considered and prioritized.

  • high prevalence of atypical delayed enhancement in Alkaptonuria
    Journal of Cardiovascular Magnetic Resonance, 2014
    Co-Authors: Marcus Y. Chen, Sujata M Shanbhag, Vandana Sachdev, Patricia W Bandettini, Peter Kellman, Andrew E Arai, Wendy J Introne
    Abstract:

    Background Alkaptonuria is a rare autosomal recessive metabolic disorder with an incidence of 1 case in 250,000 to 1 million live births. This genetic abnormality involves the tyrosine metabolism pathway which results in homogentisic acid accumulation throughout various tissues, including the heart. The purpose of this study is to prospectively determine the prevalence of cardiovascular abnormalities characterized by MRI in patients with Alkaptonuria. Methods A group of 57 consecutive adult patients with laboratory confirmed Alkaptonuria were referred for evaluation including transthoracic echocardiography and cardiac MRI, which included cine and phase contrast imaging at either 1.5T or 3T. Phase-sensitive inversion-recovery delayed enhancement imaging was performed after gadolinium-DTPA contrast administration. Late gadolinium enhancement patterns were determined by consensus read between two experienced cardiologists using a 17-segment model. Results Overall, 56 completed cine MRI, 53 received gadolinium contrast and 1 subject experienced claustrophobia precluding any imaging. Of the 56 who had CMR imaging, 77% (41 of 56) were male and the average age was 49 ± 12 years old. The prevalence of atypical delayed enhancement was 70% (37 of 53) and predominately involved the right ventricular insertion point (84%, 31 of 37 patients). Other delayed enhancement patterns included midwall (30%, 11 of 37), near aortic root (30%, 11 of 37), focal nodular (11%, 4 of 37), mitral papillary muscle involvement (8%, 3 of 37), and patchy/intermediate (5%, 2 of 37). Involvement of the right ventricular point has been associated with pulmonary hypertension; however, this group of Alkaptonuria patients had normal estimated right ventricular systolic pressures measured on echocardiography performed within 1 day (median). The number of segments with atypical delayed enhancement was 2.7 ± 1.4 per patient. The prevalence of any atypical delayed enhancement trended higher for females vs. males (86% vs. 62%, p = NS) and was not associated with age. One subject had subendocardial delayed enhancement in a coronary artery distribution consistent with myocardial infainfarction. Conclusions Myocardial fibrosis based on late gadolinium enhancement abnormalities, especially involving the right ventricle insertion site, are common in patients with Alkaptonuria despite not having pulmonary hypertension or cardiac structural abnormalities and suggests myocardial involvement due to this metabolic disorder. Further study is required to determine the etiology and clinical significance.

Chanika Phornphutkul – One of the best experts on this subject based on the ideXlab platform.

  • minocycline induced hyperpigmentation masquerading as Alkaptonuria in individuals with joint pain
    Arthritis & Rheumatism, 2004
    Co-Authors: Pim Suwannarat, Isa Bernardini, Chanika Phornphutkul, Maria L. Turner, William A Gahl
    Abstract:

    Alkaptonuria, a rare autosomal-recessive disorder caused by mutations in the HGD gene and a deficiency of homogentisate 1,2-dioxygenase, is characterized by accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue resulting in joint disease. Certain medications have been reported to cause cutaneous hyperpigmentation resembling that of Alkaptonuria. We present 5 such cases. Eighty-eight patients with a possible diagnosis of Alkaptonuria were examined at the National Institutes of Health Clinical Center between June 2000 and March 2004. The diagnosis of Alkaptonuria was confirmed or ruled out by measurement of HGA in the urine. Five patients with findings consistent with ochronosis, including pigmentary changes of the ear and mild degenerative disease of the spine and large joints, were diagnosed clinically as having Alkaptonuria, but the diagnosis was withdrawn based on normal urine HGA levels. All 5 patients were women who had taken minocycline for dermatologic or rheumatologic disorders for extended periods. Minocycline-induced hyperpigmentation should be considered in the differential diagnosis of ochronosis. This could be of increased significance now that minocycline and other tetracyclines have been proposed as therapeutic options for rheumatoid arthritis, bringing a new population of patients with ochronosis and arthritis to medical attention with the potential, but incorrect, diagnosis of Alkaptonuria.

  • Minocycline‐induced hyperpigmentation masquerading as Alkaptonuria in individuals with joint pain
    Arthritis and rheumatism, 2004
    Co-Authors: Pim Suwannarat, Isa Bernardini, Chanika Phornphutkul, Maria L. Turner, William A Gahl
    Abstract:

    Alkaptonuria, a rare autosomal-recessive disorder caused by mutations in the HGD gene and a deficiency of homogentisate 1,2-dioxygenase, is characterized by accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue resulting in joint disease. Certain medications have been reported to cause cutaneous hyperpigmentation resembling that of Alkaptonuria. We present 5 such cases. Eighty-eight patients with a possible diagnosis of Alkaptonuria were examined at the National Institutes of Health Clinical Center between June 2000 and March 2004. The diagnosis of Alkaptonuria was confirmed or ruled out by measurement of HGA in the urine. Five patients with findings consistent with ochronosis, including pigmentary changes of the ear and mild degenerative disease of the spine and large joints, were diagnosed clinically as having Alkaptonuria, but the diagnosis was withdrawn based on normal urine HGA levels. All 5 patients were women who had taken minocycline for dermatologic or rheumatologic disorders for extended periods. Minocycline-induced hyperpigmentation should be considered in the differential diagnosis of ochronosis. This could be of increased significance now that minocycline and other tetracyclines have been proposed as therapeutic options for rheumatoid arthritis, bringing a new population of patients with ochronosis and arthritis to medical attention with the potential, but incorrect, diagnosis of Alkaptonuria.

  • Natural History of Alkaptonuria
    The New England journal of medicine, 2002
    Co-Authors: Chanika Phornphutkul, Wendy J Introne, Isa Bernardini, Diana L Fitzpatrick, Monique B. Perry, Mark D. Murphey, Paul D. Anderson, Marjan Huizing, Yair Anikster, Lynn H. Gerber
    Abstract:

    Background Alkaptonuria, caused by mutations in the HGO gene and a deficiency of homogentisate 1,2-dioxygenase, results in an accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue. There is no effective therapy for this disorder, although nitisinone inhibits the enzyme that produces HGA. We performed a study to delineate the natural history of Alkaptonuria. Methods We evaluated 58 patients with Alkaptonuria (age range, 4 to 80 years), using clinical, radiographic, biochemical, and molecular methods. A radiographic scoring system was devised to assess the severity of spinal and joint damage. Two patients were treated with nitisinone for 10 and 9 days, respectively. Results Life-table analyses showed that joint replacement was performed at a mean age of 55 years and that renal stones developed at 64 years, cardiac-valve involvement at 54 years, and coronary-artery calcification at 59 years. Linear regression analysis indicated that the radiographic score for the severity …

Swetha Rajasekaran – One of the best experts on this subject based on the ideXlab platform.

  • Spontaneous tendon ruptures in Alkaptonuria.
    The Journal of bone and joint surgery. British volume, 2003
    Co-Authors: R. V. Manoj Kumar, Swetha Rajasekaran
    Abstract:

    Ochronosis, the musculoskeletal manifestation of Alkaptonuria, is known to lead to degenerative changes of the spine and weight-bearing joints. Symptoms related to degeneration of tendons or ligaments with spontaneous ruptures have not previously been reported. Three patients are described with four spontaneous ruptures of either the patellar tendon or tendo Achillis as the first symptom of Alkaptonuria.

Isa Bernardini – One of the best experts on this subject based on the ideXlab platform.

  • minocycline induced hyperpigmentation masquerading as Alkaptonuria in individuals with joint pain
    Arthritis & Rheumatism, 2004
    Co-Authors: Pim Suwannarat, Isa Bernardini, Chanika Phornphutkul, Maria L. Turner, William A Gahl
    Abstract:

    Alkaptonuria, a rare autosomal-recessive disorder caused by mutations in the HGD gene and a deficiency of homogentisate 1,2-dioxygenase, is characterized by accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue resulting in joint disease. Certain medications have been reported to cause cutaneous hyperpigmentation resembling that of Alkaptonuria. We present 5 such cases. Eighty-eight patients with a possible diagnosis of Alkaptonuria were examined at the National Institutes of Health Clinical Center between June 2000 and March 2004. The diagnosis of Alkaptonuria was confirmed or ruled out by measurement of HGA in the urine. Five patients with findings consistent with ochronosis, including pigmentary changes of the ear and mild degenerative disease of the spine and large joints, were diagnosed clinically as having Alkaptonuria, but the diagnosis was withdrawn based on normal urine HGA levels. All 5 patients were women who had taken minocycline for dermatologic or rheumatologic disorders for extended periods. Minocycline-induced hyperpigmentation should be considered in the differential diagnosis of ochronosis. This could be of increased significance now that minocycline and other tetracyclines have been proposed as therapeutic options for rheumatoid arthritis, bringing a new population of patients with ochronosis and arthritis to medical attention with the potential, but incorrect, diagnosis of Alkaptonuria.

  • Minocycline‐induced hyperpigmentation masquerading as Alkaptonuria in individuals with joint pain
    Arthritis and rheumatism, 2004
    Co-Authors: Pim Suwannarat, Isa Bernardini, Chanika Phornphutkul, Maria L. Turner, William A Gahl
    Abstract:

    Alkaptonuria, a rare autosomal-recessive disorder caused by mutations in the HGD gene and a deficiency of homogentisate 1,2-dioxygenase, is characterized by accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue resulting in joint disease. Certain medications have been reported to cause cutaneous hyperpigmentation resembling that of Alkaptonuria. We present 5 such cases. Eighty-eight patients with a possible diagnosis of Alkaptonuria were examined at the National Institutes of Health Clinical Center between June 2000 and March 2004. The diagnosis of Alkaptonuria was confirmed or ruled out by measurement of HGA in the urine. Five patients with findings consistent with ochronosis, including pigmentary changes of the ear and mild degenerative disease of the spine and large joints, were diagnosed clinically as having Alkaptonuria, but the diagnosis was withdrawn based on normal urine HGA levels. All 5 patients were women who had taken minocycline for dermatologic or rheumatologic disorders for extended periods. Minocycline-induced hyperpigmentation should be considered in the differential diagnosis of ochronosis. This could be of increased significance now that minocycline and other tetracyclines have been proposed as therapeutic options for rheumatoid arthritis, bringing a new population of patients with ochronosis and arthritis to medical attention with the potential, but incorrect, diagnosis of Alkaptonuria.

  • Natural History of Alkaptonuria
    The New England journal of medicine, 2002
    Co-Authors: Chanika Phornphutkul, Wendy J Introne, Isa Bernardini, Diana L Fitzpatrick, Monique B. Perry, Mark D. Murphey, Paul D. Anderson, Marjan Huizing, Yair Anikster, Lynn H. Gerber
    Abstract:

    Background Alkaptonuria, caused by mutations in the HGO gene and a deficiency of homogentisate 1,2-dioxygenase, results in an accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue. There is no effective therapy for this disorder, although nitisinone inhibits the enzyme that produces HGA. We performed a study to delineate the natural history of Alkaptonuria. Methods We evaluated 58 patients with Alkaptonuria (age range, 4 to 80 years), using clinical, radiographic, biochemical, and molecular methods. A radiographic scoring system was devised to assess the severity of spinal and joint damage. Two patients were treated with nitisinone for 10 and 9 days, respectively. Results Life-table analyses showed that joint replacement was performed at a mean age of 55 years and that renal stones developed at 64 years, cardiac-valve involvement at 54 years, and coronary-artery calcification at 59 years. Linear regression analysis indicated that the radiographic score for the severity …