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Keratan and Heparan Sulfaturia: Glucosamine-6-Sulfate Sulfatase Deficiency REUBEN MATALON, M.D., Ph .D.,* REBECCA WAPPNER, M.D.,T MINERVA DEANCHING, M.S.,* IRA K

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Keratan and Heparan Sulfaturia: Glucosamine-6-Sulfate Sulfatase Deficiency REUBEN MATALON, M.D., Ph .D.,* REBECCA WAPPNER, M.D.,T MINERVA DEANCHING, M.S.,* IRA K ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 12, No. 3 Copyright © 1982, Institute for Clinical Science, Inc. Keratan and Heparan Sulfaturia: Glucosamine-6-Sulfate Sulfatase Deficiency REUBEN MATALON, M.D., Ph .D.,* REBECCA WAPPNER, M.D.,t MINERVA DEANCHING, M.S.,* IRA K. BRANDT, M.D.,f and ALLEN HORWITZ, M.D., Ph .D.* * Department of Pediatrics, Hospital Laboratories, Abraham Lincoln School of Medicine, University of Illinois, Chicago, IL 60612 f Indiana University, Bloomington, IN 47402 \University of Chicago, Chicago, IL 60637 ABSTRACT The pattern of excretion of urinary acid mucopolysaccharides (AMPS) has been helpful to establish the diagnosis of mucopolysaccharidoses. The im­ portance of urine analysis for AMPS and the specific enzyme assays is exemplified in a 3V2 year old Caucasian male with severe mental retardation, small stature, thoracolumbar kyphosis, and dysostosis multiplex. Urine anal­ ysis for AMPS revealed excessive quantities of keratan and heparan sulfate. This mucopolysacchariduria was not associated with hepatosplenomegaly or corneal clouding. Enzymic studies on cultured skin fibroblasts indicated deficiency of N-acetylglucosamine-6-sulfate sulfatase. This enzyme defi­ ciency is different from that responsible for Morquio’s syndrome, and early recognition is essential for proper counseling. Introduction zymatic studies in addition to urine AMPS determination. The enzymic and urine Since the discovery that excessive AMPS heterogeneity of some of the muco­ quantities of acid mucopolysaccharides polysaccharidoses are summarized in ta­ (AMPS) are excreted in the urine of pa­ ble I. It is apparent from the diseases de­ tients with Hurler’s syndrome,4 it became scribed in this table that different enzyme clear that different enzyme defects may defects are responsible for excessive ex­ result in the same mucopolysaccharidu­ cretion of the same AMPS. For example, ria. It was apparent that the diagnostic in the Hurler and Hunter syndromes, der- aids for such patients should include en­ matan and heparan sulfate are excreted, 234 0091-7370/82/0500-0234 $00.90 © Institute for Clinical Science, Inc. KERATAN AND HEPARIN SULFATURIA 235 while in the various Sanfilippo syn­ TABLE I dromes, only haparan sulfate is excreted The Mucopolysaccharidoses in the urine.1,5'7,10,11,17 The excretion of keratan and heparan Urinary Muco- Enzyme sulfates in the urine is yet another syn­ Disease polysaccharides Deficiency drome characterized by N-acetylglucosam- Hurler syndrome Dermatan sulfate ct-L-Iduronidase ine-6-sulfate sulfatase deficiency.16 Such Heparan sulfate (D/H)* Scheie syndrome Dermatan. sulfate a-L-Iduronidase an enzyme defect has been suggested in a (D)t Hurler Scheie Dermatan sulfate a-L-Iduronidase patient of DiFerrante et al.2 However, ex­ "compound” (D) t amination of the cultured fibroblasts of Hunter syndrome Dermatan sulfate Iduronosulfate Heparan sulfate sulfatase DiFerrante’s patient revealed sulfamidase Sanfilippo Heparan sulfate Sulfamidase deficiency and normal activity of N- syndrome A Sanfilippo Heparan sulfate a-N-Acetylglucos- acetylglucosamine-6-sulfate sulfatase. Re­ syndrome B aminidase Sanfilippo Heparan sulfate Acetyl CoA: cently, DiFerrante3 has indicated that on syndrome C a-glucosaminide re-evaluation his patient did not, in fact, N-acetyl-trans- ferase have N-acetylglucosamine-6-sulfate sul­ Sanfilippo Heparan sulfate N-Acetylglucos- fatase deficiency. syndrome D amine-6 -sulfate sulfatase (specific for heparan sulfate Case Report only) The patient, B.J.V., a 3’/2 year old Caucasian male, Morquio Keratan sulfate N-Acetylgalac- syndrome A Chondroitin-6 - tosamine-6 -sul- was the product of an uncomplicated pregnancy. De­ sulfate fate sulfatase velopmental milestones seemed appropriate during and galactose- the first year of life. At 18 months of age, deteriora­ 6 -sulfatase tion of motor skills and somatic deformities such as Morquio Keratan sulfate B-Galactosidase syndrome B gibbus, pectus excavatum, prominence of the me- Maroteaux-Lamy Dermatan sulfate N-Acetylgalac- topic suture, and X-ray findings of dysostosis multi­ syndrome tosamine 4-sul­ plex became evident. At the age of three years, petit fate sulfatase mal seizures started; at 3% years, the child became (Aryl sulfatase blind and was virtually unresponsive. This rapid B) B-Glucuronidase Dermatan sulfate S-Glucuronidase mental deterioration was not associated with cor­ deficiency Heparan sulfate neal clouding, hepatosplenomegaly, or coarse facial Keratan and Keratan sulfate N-Acetylglucos- features. heparan Heparan sulfate amine-6 -sulfate sulfaturia sulfatase (specific for Methods keratan sulfate and heparan Urinary AMPS were isolated using gel sulfate) chromatography with Sephadex G-25 fol­ *D/H indicates iduronidase deficiency for iduronide lowed by precipitation with cetylpyridin- linkages in dermatan (D) and heparan (H) sulfates +D indicates iduronidase deficiency for iduronide ium chloride.5 Heparan sulfate and kera­ linkages in dermatan sulfate only tan sulfate were eluted from Dowex 1x2, Cl-, with step wise increase in concentra­ tions of NaCl, 1.25 M eluted heparan sul­ The keratan sulfate fraction eluted with fate, and 4.0 M eluted keratan sulfate.18 4.0 N NaCl was further characterized by The heparan sulfate fraction was charac­ the lack of N-sulfated hexosamine, the re­ terized by the presence of N-sulfated sistance to chondroitinase digestion, the hexosamine, as determined by the nitrous earbazole to hexosamine ratio of 0.26, the acid reaction,12 the resistance to digestion sulfate to hexosamine ratio of 1.04, and with chondroitinases, and the presence of the presence of glucosamine as the major glucosamine as the major amino sugar in amino sugar (93 percent). The enzyme this fraction (>95 percent). Amino acids deficient in Morquio’s syndrome, N-ace- were anlyzed.* tylgalactosamine-6-sulfate sulfatase, was assayed with a trisaccharide prepared from * Beckman M 121 amino acid analyzer was used. chondroitin- 6 - sulfate: N - acetylgalacto- 236 MATALON, WAPPNER, DEANCHING, BRANDT, AND HORWITZ samine-6-sulfate (/3, 1—>4)-glucuronic acid- TABLE II (/3, 1—>3) - {l-3H}-N-galactosaminitol-6 Urinary Acid Mucopolysaccharides -sulfate.6,8 Chondroitin-6-sulfate was di­ gested with testicular hyaluronidase and Chrondroit in Keratan Heparan the tetrasaccharide fraction was isolated Total AMPS Sulfates* Sulfate Sulfatei by gel chromatography on Sephadex G-25. mg/24 h percent percent percent Normal (n-31) 2.5i 0.8 95 < 2 < 3 The tetrasaccharide was further digested Patient B.J.V. 14.0 15 65 20 Morquio type A 25.0± 5.5 57 40 < 3 with /3-glucuronidase, and the resulting (n=12) trisaccharide was isolated and labeled Sanfilippo 40.0+10.5 12 < 3 85 with tritiated borohydride. type A (n=21) *Dermatan sulfate comprised less than two percent of the N-Acetylglucosamine-6-sulfate sulfa­ fraction. tase, the enzyme deficient in our patient, tBased on N-sulfated hexosamine. was measured with a keratan sulfate de­ rived disaccharide: N-acetylglucosamine- 6-sulfate-/3, 1—>4-{l-3H} galactitol. Low Results sulfated keratan sulfate was isolated from human rib cartilage, treated with /3-endo- Acid mucopolysaccharides in the urine galactosidase and monosulfated disaccha­ are shown in table II. The urinary AMPS ride, was isolated and labeled with trit­ of our patient (B.J.V.) with keratan and iated borohydride.9 heparan sulfaturia are compared with nor­ Enzyme extracts were prepared from mal, Morquio, and Sanfilippo patients. cultured skin fibroblasts grown in modi­ Because of the presence of keratan sulfate fied Eagle medium.15 Cells were dis­ in urine, N-acetylgalactosamine-6-sulfate rupted by sonication and centrifuged at sulfatase, the enzyme deficient in Mor­ 10,000 x g for 10 min; the supernatant was quio syndrome, was assayed using cul­ used for enzymic activity following dial­ tured skin fibroblasts. The results of these ysis against 0.05 M sodium acetate, pH studies, indicated in table III, showed no 5.0. Each incubation mixture contained deficiency of that enzyme activity. In ad­ 40 to 50 ¡A of extract, 5.5 /¿moles (100,000 dition, other lysosomal enzyme activites, cpm) of substrate, 20 fig of bovine serum including /3-galactosidase, were normal. albumin, and 9 jamóle of sodium acetate, The specific enzyme deficiency, N-ace- pH 6.0, in a final volume of 100 fi 1. tylglucosamine-6-sulfate sulfatase, which The activity for N-acetylgalactosamine- is unique to patient B.J.V., is indicated in 6-sulfate sulfatase was determined as the table III. Mixing experiments of fibro­ rate of production of nonsulfated trisac­ blasts from patient B.J.V. and normal charide from the disulfated {3H}-labeled fibroblasts showed no endogenous inhibi­ chondroitin-6-sulfate trisaccharide. tor for N-acetylglucosamine-6-sulfate sul- The activity for N-acetylglucosamine-6- sulfate sulfatase was determined as that TAB L E III fraction of radioactivity which did not Activities of N-Acetylglucosamine-6-sulfatase bind to Dowex 1x2, Cl~, following and N-Acetylgalactosamine-6-sulfatase in the incubation of the tritiated galactitol- Fibroblast Extracts N-acetylglucosamine-6-sulfate with the N-Acetylgalactos- amine-6-sulfate N-Acetyl glucosamine proper enzyme extract. Since Dowex 1 x Sulfatase 6-sulfate Sulfatase 2, Cl- binds anionic compounds, the hy­ drolysis of the sulfate groups results in the pmole/itig protein/hr pmole/mg protein/hr Normal 516 83 recovery of the nonsulfated disaccharide Patient B.J.V. 610 Not detectable in the effluent, while the non reacted ma­ Marguio A 26 90 terial binds to the Dowex column. Sanfilippo A 510 86 KERATAN AND HEPARIN SULFATURIA 237 fatase. Fibroblast extracts from the patient a-L-iduronidase. A situation analogous to of DiFerrante had normal activity for both a-L-iduronidase may exist with N-acetyl- hexosamine-6-sulfatases.2 glucosamine-6-sulfate sulfatase. A defici­ ency in the activity of an isoenzyme spe­ cific for the hydrolysis of sulfate from Discussion and Conclusions carbon 6 in the N-acetylglucosamine in The clinical coürse of this patient with heparan sulfate leads to Sanfilippo D and keratan and heparan sulfaturia is rather heparan sulfaturia.
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