Correspondence

Urinary Pyridinium Cross-Links: A Noninvasive Diagnostic Test for Ehlers-Danlos Syndrome Type VI

N Engl J Med 1994; 331:132-133July 14, 1994

Article

To the Editor:

Ehlers-Danlos syndrome type VI is an autosomal recessive disorder of connective tissue caused by mutations in the gene for collagen lysyl hydroxylase. This enzyme hydroxylates lysyl residues on newly synthesized intracellular collagen peptides, and its impairment results in a low hydroxylysine content in mature collagen1,2. Diagnosis has required a large skin-biopsy specimen to demonstrate reduced amounts of hydroxylysine in skin collagen and defective lysyl hydroxylase in cultured skin fibroblasts. Here, we report that measurement of the urinary excretion of pyridinium cross-links serves as a simple, noninvasive diagnostic test for this disorder.

After extracellular secretion, specific lysyl and hydroxylysyl residues on adjacent collagen fibrils interact to produce pyridinium cross-links3. After degradation of collagen, two forms of stable pyridinium cross-links are found in urine: pyridinoline, a more abundant component derived from three hydroxylysine residues, and deoxypyridinoline, normally a less abundant component derived from one lysine and two hydroxylysine residues3,4.

We measured the urinary excretion of pyridinium cross-links in 4 patients with Ehlers-Danlos syndrome type VI and 71 normal subjects (Table 1Table 1Urinary Excretion of Pyridinium Cross-Links in Four Patients with Ehlers-Danlos Syndrome Type VI.). The pyridinium cross-links were extracted from hydrolysates of urine and analyzed by reverse-phase high-performance liquid chromatography with the use of a fluorescence detector4. The ratio of deoxypyridinoline to pyridinoline in the urine of normal subjects ranged from 0.16 to 0.37 in all age groups. The patients with Ehlers-Danlos syndrome type VI had increased urinary deoxypyridinoline excretion, with a consequent increase in the ratio of deoxypyridinoline to pyridinoline (range, 4.9 to 7.1). In patients with other types of Ehlers-Danlos syndrome, such as types I, II, and IV, the excretion of pyridinium cross-links and the ratio of deoxypyridinoline to pyridinoline were within the normal range (data not shown). In patients with other bone diseases, such as osteoporosis and Paget's disease, the excretion of pyridinoline and deoxypyridinoline was increased, but the ratio was less than 0.54,5.

We conclude that the extraordinarily high ratio of deoxypyridinoline to pyridinoline in urine from patients with Ehlers-Danlos syndrome type VI results from a reduced number of hydroxylated lysyl residues and consequent uniquely altered cross-link formation in mature collagen.

Marzia Pasquali, Ph.D.
Philip P. Dembure, Ph.D.
Maria J. Still, M.S.
Louis J. Elsas, M.D.
Emory University School of Medicine, Atlanta, GA 30322

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Citing Articles (10)

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   Tomoki Kosho, Jun Takahashi, Hirofumi Ohashi, Gen Nishimura, Hiroyuki Kato, Yoshimitsu Fukushima. (2005) Ehlers-Danlos syndrome type VIB with characteristic facies, decreased curvatures of the spinal column, and joint contractures in two unrelated girls. American Journal of Medical Genetics Part A 138A:3, 282-287
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   Karin Mayer, Christoph Marschall. (2005) Molekulargenetische Diagnostik von Bindegewebserkrankungen Molecular genetic analysis of connective tissue disorders. LaboratoriumsMedizin 29:3, 176-193
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   Richard J. Wenstrup, Leah B. Hoechstetter. 2005. Ehlers-Danlos Syndromes. .
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   Karen Munday. (2003) Vitatmin C and bone markers: investigations in a Gambian population. Proceedings of the Nutrition Society 62:02, 429-436
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   Harumi Tsuchiya, C. J. Bates. (2003) Comparison of vitamin C deficiency with food restriction on collagen cross-link ratios in bone, urine and skin of weanling guinea-pigs. British Journal of Nutrition 89:03, 303
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   David Eyre, Ping Shao, Mary Ann Weis, Beat Steinmann. (2002) The kyphoscoliotic type of Ehlers–Danlos syndrome (type VI): differential effects on the hydroxylation of lysine in collagens I and II revealed by analysis of cross-linked telopeptides from urine. Molecular Genetics and Metabolism 76:3, 211-216
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   Richard J. Wenstrup, Richard A. Meyer, Jennifer S. Lyle, Leah Hoechstetter, Peter S. Rose, Howard P. Levy, Claire A. Francomano. (2002) Prevalence of aortic root dilation in the Ehlers-Danlos syndrome. Genetics in Medicine 4:3, 112-117
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   Heather N. Yeowell, Linda C. Walker. (2000) Mutations in the Lysyl Hydroxylase 1 Gene That Result in Enzyme Deficiency and the Clinical Phenotype of Ehlers–Danlos Syndrome Type VI. Molecular Genetics and Metabolism 71:1-2, 212-224
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    J. Marowska, M. Kobylińska, J. Łukaszkiewicz, A. Tałajko, B. Rymkiewicz-Kluczyńska, R.S. Lorenc. (1996) Pyridinium crosslinks of collagen as a marker of bone resorption rates in children and adolescents: Normal values and clinical application. Bone 19:6, 669-677
    CrossRef