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References 1. Castro Magana M, Angulo M, Fuentes B, Castelar ME, Canas A, Espinoza B (1986) Effect of prolonged clonidine administration on growth hormone concentrations and rate of linear growth in children with constitutional growth delay. J Pediatr 109 : 784-787 2. Nakamoto JM, Gertner JM, Press CM, Hintz RL, Rosenfeld RG, Genel M (1986) Suppression of the growth hormone (GH) response to clonidine and GH-releasing hormone by exogenous GH. J Clin Endocrinol Metab 62 : 822-826 3. Pintor C, Cella SG, Loche S, Puggioni R, Corda R, Locatelli V, Muller EE (1987) Clonidine treatment for short stature. Lancet I: 1226-1229 4. Rosenbaum M, Loche S, Balzano S, Gertner JM (1988) Shortterm met-hGH infusion inhibits somatotroph response to growth hormone releasing hormone (1-44). Metabolism 37 : 131-135 5. Rosenthal SM, Hulse JA, Kaplan SL, Grumbach MM (1986) Exogenous growth hormone inhibits growth hormone-releasing factor induced growth hormone secretion in normal men. J Clin Invest 77 : 176-180 6. Sartorio A, Spada A, Conti A, Morabito F, Faglia G (1990) Effect of two consecutive administrations of GHRH in children with constitutional growth delay. Eur J Pediatr 149 : 678-679 7. Sherman BM (1989) Idiopathic short stature - Results of a oneyear controlled study of human growth hormone treatment. J Pediatr 115:713-719 8. Wu RHK, St.Louis Y, DiMartino-Nardi J, Wesoly S, Sobel EH, Sherman B, Saenger P (1990) Preservation of physiological growth hormone (GH) secretion in idiopathic short stature after recombinant GH therapy. J Clin Endocrinol Metab 70:16121615
of homogentisic acid excreted in urine. More recently the effects of ascorbic acid on the excretion of homogentistic acid and its derivative benzoquinone acetic acid were studied [5]. The ability of ascorbic acid to cause the disappearance of benzoquinone acetic acid suggests its possible use in the prevention of ochronosis in patients with alkaptonuria. Definitive proof of efficacy will require a long-term study on a large number of patients with alkaptonuria but an animal model provides additional evidence of the probable efficacy of ascorbic acid therapy. During a metabolic screening programme of inbred and mutant strains of mice we discovered a mutation producing alkaptonuria (X. Montagutelli and J.L. Guenet unpublished results). Biochemical analysis revealed homogentisic aciduria (550gmol/mmol creatinine) and an undetectable homogentisic oxidase activity [2] in liver. A pathological examination of a 14-monthold mouse showed no pigment deposits in the tissues (knee and hip articular cartilage, intervertebral disks, tendons and articular soft tissues). The lack of ochronosis in alkaptonuric mice may be explained by the endogenous production of ascorbic acid by mice (33.6-275.0 mg/ kg per day) [3], since this amount is in the same range as the ascorbic acid therapy used by Wolf et al. [5] for human alkaptonuria (100 mg/kg per day).
References
Ascorbic acid and alkaptonuria P. K a m o u n 1, M. Coude 1, M. Forest 2, X. Montagutelli 3, and J. L. G u e n e t 3 1Laboratofie de Biochimie M6dicale B, H6pital Necker, F-75743 Paris, Cedex 15, France 2Laboratoire d'Anatomie Pathologique, H6pital Cochin, F-75014 Paris, France 3Institut Pasteur, F-75724 Paris, Cedex 15, France Received August 20, 1991 ! Accepted August 20, 1991
Sir: Alkaptonuria is a rare inborn error of tyrosine metabolism in which deficient activity of homogentisic acid oxidase produces an accumulation of homogentisic acid and leads to debilitating ochronotic arthritis in adulthood [1]. Homogentisic acid is thought to cause ochronotic arthritis following its oxidation to labile benzoquinone acetic acid which then either binds directly or after formation of a polymer to biological components such as collagen [6]. In 1940 Sealock et al. [4] studied the use of ascorbic acid for the treatment of a patient with alkaptonuria but vitamin C therapy did not reduce the amount
1. Bunin JJ, McGuire TF, Laster L, La Du BN, Seegmiller JE (1957) Alkaptonuria: clinical staff conference at the National Institutes of Health. Ann Int Med 47 : 1210-1224 2. La Du BN, Zannoni VG, Laster L, Seegmiller JE (1958) The nature of the defect in tyrosine metabolism in alkaptonuria. J Biol Chem 230 : 251-260 3. Levine M (1986) New concepts in the biology and biochemistry of ascorbic acid. N Engl J Med 314 : 892-902 4. Sealock RR, Galdston M, Steele JM (1940) Administration of ascorbic acid to an alkaptonuria patient. Proc Soc Exp Biol Med 44 : 580-583 5. Wolff JA, Barshop B, Nyhan WL, Lesli J, Seegmiller JE, Gruber H, Garst M, Winter S, Michals K, Matalon R (1989) Effects of ascorbic acid in alkaptonuria: alterations in benzoquinone acetic acid and an ontogenic effect in infancy. Pediatr Res 26: 140-144 6. Zannoni VG, Lomtevas V, Goldfinger S (1969) Oxidation of homogentisic acid to ochronotic pigment in connective tissue. Biochim Biophys Acta 177 : 94-105
References 1. Castro Magana M, Angulo M, Fuentes B, Castelar ME, Canas A, Espinoza B (1986) Effect of prolonged clonidine administration on growth hormone concentrations and rate of linear growth in children with constitutional growth delay. J Pediatr 109 : 784-787 2. Nakamoto JM, Gertner JM, Press CM, Hintz RL, Rosenfeld RG, Genel M (1986) Suppression of the growth hormone (GH) response to clonidine and GH-releasing hormone by exogenous GH. J Clin Endocrinol Metab 62 : 822-826 3. Pintor C, Cella SG, Loche S, Puggioni R, Corda R, Locatelli V, Muller EE (1987) Clonidine treatment for short stature. Lancet I: 1226-1229 4. Rosenbaum M, Loche S, Balzano S, Gertner JM (1988) Shortterm met-hGH infusion inhibits somatotroph response to growth hormone releasing hormone (1-44). Metabolism 37 : 131-135 5. Rosenthal SM, Hulse JA, Kaplan SL, Grumbach MM (1986) Exogenous growth hormone inhibits growth hormone-releasing factor induced growth hormone secretion in normal men. J Clin Invest 77 : 176-180 6. Sartorio A, Spada A, Conti A, Morabito F, Faglia G (1990) Effect of two consecutive administrations of GHRH in children with constitutional growth delay. Eur J Pediatr 149 : 678-679 7. Sherman BM (1989) Idiopathic short stature - Results of a oneyear controlled study of human growth hormone treatment. J Pediatr 115:713-719 8. Wu RHK, St.Louis Y, DiMartino-Nardi J, Wesoly S, Sobel EH, Sherman B, Saenger P (1990) Preservation of physiological growth hormone (GH) secretion in idiopathic short stature after recombinant GH therapy. J Clin Endocrinol Metab 70:16121615
of homogentisic acid excreted in urine. More recently the effects of ascorbic acid on the excretion of homogentistic acid and its derivative benzoquinone acetic acid were studied [5]. The ability of ascorbic acid to cause the disappearance of benzoquinone acetic acid suggests its possible use in the prevention of ochronosis in patients with alkaptonuria. Definitive proof of efficacy will require a long-term study on a large number of patients with alkaptonuria but an animal model provides additional evidence of the probable efficacy of ascorbic acid therapy. During a metabolic screening programme of inbred and mutant strains of mice we discovered a mutation producing alkaptonuria (X. Montagutelli and J.L. Guenet unpublished results). Biochemical analysis revealed homogentisic aciduria (550gmol/mmol creatinine) and an undetectable homogentisic oxidase activity [2] in liver. A pathological examination of a 14-monthold mouse showed no pigment deposits in the tissues (knee and hip articular cartilage, intervertebral disks, tendons and articular soft tissues). The lack of ochronosis in alkaptonuric mice may be explained by the endogenous production of ascorbic acid by mice (33.6-275.0 mg/ kg per day) [3], since this amount is in the same range as the ascorbic acid therapy used by Wolf et al. [5] for human alkaptonuria (100 mg/kg per day).
References
Ascorbic acid and alkaptonuria P. K a m o u n 1, M. Coude 1, M. Forest 2, X. Montagutelli 3, and J. L. G u e n e t 3 1Laboratofie de Biochimie M6dicale B, H6pital Necker, F-75743 Paris, Cedex 15, France 2Laboratoire d'Anatomie Pathologique, H6pital Cochin, F-75014 Paris, France 3Institut Pasteur, F-75724 Paris, Cedex 15, France Received August 20, 1991 ! Accepted August 20, 1991
Sir: Alkaptonuria is a rare inborn error of tyrosine metabolism in which deficient activity of homogentisic acid oxidase produces an accumulation of homogentisic acid and leads to debilitating ochronotic arthritis in adulthood [1]. Homogentisic acid is thought to cause ochronotic arthritis following its oxidation to labile benzoquinone acetic acid which then either binds directly or after formation of a polymer to biological components such as collagen [6]. In 1940 Sealock et al. [4] studied the use of ascorbic acid for the treatment of a patient with alkaptonuria but vitamin C therapy did not reduce the amount
1. Bunin JJ, McGuire TF, Laster L, La Du BN, Seegmiller JE (1957) Alkaptonuria: clinical staff conference at the National Institutes of Health. Ann Int Med 47 : 1210-1224 2. La Du BN, Zannoni VG, Laster L, Seegmiller JE (1958) The nature of the defect in tyrosine metabolism in alkaptonuria. J Biol Chem 230 : 251-260 3. Levine M (1986) New concepts in the biology and biochemistry of ascorbic acid. N Engl J Med 314 : 892-902 4. Sealock RR, Galdston M, Steele JM (1940) Administration of ascorbic acid to an alkaptonuria patient. Proc Soc Exp Biol Med 44 : 580-583 5. Wolff JA, Barshop B, Nyhan WL, Lesli J, Seegmiller JE, Gruber H, Garst M, Winter S, Michals K, Matalon R (1989) Effects of ascorbic acid in alkaptonuria: alterations in benzoquinone acetic acid and an ontogenic effect in infancy. Pediatr Res 26: 140-144 6. Zannoni VG, Lomtevas V, Goldfinger S (1969) Oxidation of homogentisic acid to ochronotic pigment in connective tissue. Biochim Biophys Acta 177 : 94-105
