TYPE IV glycogen storage disease is a rare autosomal recessive disorder (also called Andersen's disease1 or amylopectinosis) in which the activity of branching enzyme alpha-1, 4-glucan: alpha-1, 4-glucan 6-glucosyltransferase is deficient in the liver as well as in cultured skin fibroblasts and other tissues.2,3 This branching enzyme is responsible for creating branch points in the normal glycogen molecule. In the relative or absolute absence of this enzyme, an insoluble and irritating form of glycogen, an amylopectin-like polysaccharide that resembles plant starch, accumulates in the cells. The amylopectin-like form is less soluble than normal glycogen, with longer outer and inner chains. © 1991, Massachusetts Medical Society. All rights reserved

Andreas Tzakis

Bannayan

Barbara I. Brown

Brown

Eduardo Yunis

Greene

Illingworth

Ishihara

Mazzaferro

McMaster

Reed

Rick Selby

Ross S. Kendall

Schochet

Stand

Starzl

Thomas E. Starzl

English

PubMed

Selby, R

Starzl, TE

Yunis, E

Tzakis, A

Brown, BI

Kendall, RS

D-Scholarship@Pitt

BRIEF REPORT LIVER TRANSPLANTATION FOR TYPE IV GLYCOGEN STORAGE DISEASE RICK SELBY, M.D., THOMAS E. STARZL, M.D., PH.D., EDUARDO YUNIS, M.D., BARBARA 1. BROWN, PH.D., Ross S. KENDALL, M.D., AND ANDREAS TZAKIS, M.D. T YPE IV glycogen storage disease is a rare autoso-mal recessive disorder (also called Andersen's dis-easel or amylopectinosis) in which the activity of branching enzyme alpha-I, 4-g1ucan: alpha-I, 4-g1u-can 6-g1ucosyltransferase is deficient in the liver as well as in cultured skin fibroblasts and other tissues.2,3 This branching enzyme is responsible for creating branch points in the normal glycogen molecule. In the relative or absolute absence of this enzyme, an insolu-ble and irritating form of glycogen, an amylopectin-like polysaccharide that resembles plant starch, accu-mulates in the cells. The amylopectin-like form is less soluble than normal glycogen, with longer outer and mner chains and fewer branch points. The clinical onset of the disease is insidious, with nonspecific From the Depanments of Surgery and Pathology. Children's Hospital of the UmversIty Health Center or Pittsburgh, university of Pittsburgh (R.S .. T.E.S .. E. Y .. A.T.;; the Depanmem of Biochemistry, Washington University School at \1edicine. St. Louis lB. [B. I: and the Marv Bridge Children'S Hospital. Tacoma. Wash. IR.S.K.I. Address reprint requests to Dr. Starz! at the Department of Surgery, Untversitv "r Pittsburgh. 3601 Fifth Ave., Pittsburgh. PA 15213. Supponed by grants from the Department of Veterans Affairs and by " project srant IDK 29961) from the Nalionallnsntutes of Health. gastrointestinal symptoms at first, followed by pro-gressive hepatosplenomegaly, portal hypertension, as-cites, and hepatic failure. Children with this disorder usually die of hepatic cirrhosis by the age of two to four years.4-8 In exceptional cases, cardiomyopa-thy,5-7,9 neurologic syndromes - including tremors, seizures, and dementia1o,11 - or variable manifesta-tions of myopathy5.12,13 have been reported. In pa-tients with these unusual symptoms, the clinical onset is frequently later than in typical cases, and death most often results from cardiac failure. Liver transplantation for Type IV glycogen stora.ge disease was attempted in 1972; the recipient died 110 days later after the rejection of the first liver trans-plant and attempted retransplantation. 14 Liver trans-plantation was first performed successfully in Septem-ber 1984 in Patient 1 of this series; since that time we have treated six more such patients. Our experience with these seven patients forms the basis of this report. CASE REpORTS All the patients were boys. including- two sets of brothers (Table I). All had progressive liver failure with massIve hepatomegalv, splenome'Salv, and ascites. lBeca'use patients with Tvpe IV glyco· gen storage rlisease but without pro~ressive liver disease have occa-sionallv been reported, i6 pro'5ressive liver disease was a condition for transplantation in each case.) Two of the seven patients died i Clnd 36 davs after liver transplantation - from a bowel perforation and thrombosis of the hep:ltic artery, respectively. The jive other recipients 171 percent) are healthy and have normal liver lunction 16 (0 73 months after transpiantation. The five transplant recipIents who ,urvived were hospitalized for 26 to 49 days Imean. +0). The mean (=:SD) cost of transplantation in these five patients. including all professional lees, was ~ 107 ,900±30.000. Rehospitalization was Reprinted from the New England Journal of Medicine 324:39-42 (January 3), 1991 //?; 40 THE NEW ENGLAND JOURNAL OF MEDICI:-lE Jan. 3, 1991 !lOt required except for follow-up !)ercuraneous needle biopsies of the :iVf:'i. peri()rrneci 1 TO +5 nlonths ~lfter cransplantJ.ticn, 1)1' :raLS-jugular enJomvoc:udial biopsies. performed :3 weeks w 54 months atier transplantation (Table 2). The transplantations and tallow-up biopsies were undertaken with informed parental consent. The bi-opsy procedures were considered essential for optimal care of the patients and were not part of a prospective experimentai design. Height. weight, gross and tine motor development. and language ability were retarded in all patients before transplantation. The physical strength and mOlor skills of tbe five survivors improved steadily alter transplantation. All have had a normal growth rate, two are performing well in elementary school, and the three in preschool have no apparent abnormalities in intellectual develop-ment. None has had any cardiac symptoms or any evidence of abnormalities on chest films or electrocardiographic and echocar-diographic examinations. A magnetic resonance imaging scan of the heart in one child was normal more than four years aftcr trans-plantation. METHODS Liver Transplantation The diseased liver was totally excised and replaced with a size-matched cadaveric liver, which was revascularized in an anatomi-cally normal manner and provided biliary drainage with a Roux-eu-Y choledochojej unostomv. 17 Immunosuppressive therapy con-sisted of cyclosporine and prednisone. The daily maimcnance dose of prednisone in the five surviving patients was 5 mg or less. Tissue Studies Cultured skin fibroblasts and homogenates of liver tissue from the patients were assayed at Washington University for branching-enzyme activity. The phosphorylase-coupled assay measured the rate of formation of inorganic phosphate from glucose-I-phosphate as glucose was polymerized to glycogen by the tissue homoge-nates. J ,6,1S The branching-enzyme activity in skin fibroblasts aver-aged 0.08 fLmol of inorganic phosphate per minute per milligram of protein, which was less than 10 percent of the activity in normal subjects (Table I). Amylopectin was sought on light-microscopical examination in the excised livers, in liver-biopsy samples obtained after transplan-tation, and in other tissues obtained at the time of transplantation or at autopsy. The characteristic inclusions were positive on period-ic acid-Schiff staining after digestion with diastase (PAS-D). Elec-tron-microscopical studies demonstrated the fibrillar aggregations that are tvpical of amylopectin. '"-20 Morphometric studies were performed on PAS-D-stained myo-cardial tissue obtained at autopsy from one patient and endomyo-cardial-biopsy samples from three others obtained at various times Table 1, Clinical Data on Patients with Type IV Glycogen Storage Disease Who Underwent Liver Transplantation. SK1N·FIBROBLAST PATIENT ,'\GE AT TRA.NS- BRANCHING-ENZYME DATE OF :KfoKD~ PLANTATION -\CTIYITyt OPERA nON ,"0 jKgKmoflminfm~ 31 0.10 916184 II 0.07 ~1OU1Up 36 0.11 915'85 .. .)6 1).11 1l/2SIR5 "" 1),08 :0124187 ') ::0 0.06 jl21 i R9 34 0.09 5/26189 'PatH::nts I Jnci tJ were brothers. as were Patients J and 5. LENGTH Of SURVIVAL 73 rno Died 7 days after transplantation Died 36 days aiter "ansplantation 58 rna 35 rna :8 rna :6 rno "Norma! branching-enzyme activity in skin fibroblasts. i to 2 ~mog per minute per millIgram It protem. ;.15 table 2. Deposits Positive on Periodic Acid-Schiff Staining after Digestion with Diastase (PAS-C) in the Myocardium of Four Pa-tients with Type IV Glycogen Storage Disease after Liver Transplantation. PA TlENT No. 7 TIME AFTER TRANSPLAN-T ATION rno 54.0 1.2 (at autopsy) 0.9 14.0 1.0 11.0 No. OF INCLUSIONS per 3.6xJ05 jJ.l112 24 46 332 129 Too few to quantitate Too few to quantitate MEAN AREA MEAN SIZE OCCUPIED BY OF INCLU-INCLUSIONS SIONS % IJ • .m 2 05 140 2 141 13 146 5.9 164 after transplantation (Table 2). with the Bioquant System IV (R&M Biometrics. Nashville) used for automated image analysis. Tbe biopsy samples were also separately evaluated with the point-count technique. To eliminate artifacts caused by vessel" or com-pression, interstitial and vascular spaces in the field were eliminated from the final calculations of the area of amylopectin deposition. Variation within samples was studied in 24 tields rrn~ a large piece of left ventricle obtained at autopsy from Patient 3. All the fields had much the same amylopectin distribution, with the single excep-tion of a superficial subendocardial field that contained little muscle. RESULTS There was no trace of amylopectin in the graft of the child who died 36 days after transplantation from hepatic-artery thrombosis or in the liver-biopsy speci-mens obtained from the five surviving children 1 to 45 months after transplantation. The biopsy specimens also showed no evidence of rejection. Amylopectin deposits were found in all biopsy specimens of skin (including arrectores pilorum mus-cles), jejunum, and skeletal muscle obtained at the time of transplantation. Postmortem studies in Pa-tient 3, who died 36 days after transplantation at 36 months of age, showed amylopectin in the esophagus, bowel, bladder smooth muscle, skeletal muscle, cen-tral nervous system, peripheral nerves, and heart. In this patient, amylopectin occupied about 2 percent of the myocardial area (Table 2). Myocardial samples were available from three other patients (Table 2). Patient I, whose liver was replaced when he was 36 months old, had a nearly amylopec-tin-free mvocardial-biopsy specimen 54 months later. His younger brother (Patient 6) had involvement of 13 percent of the myocardial area three weeks after trans-plantation (Table 2). A year later, the amount of amy-lopectin had been reduced to 5.9 percent (Fig. I, Ta-ble 2). In Patient 7, the mvocardial-biopsv specimen obtained one month after liver transplantation showed very few deposits in the myocvtes; 10 months later, there was no change. DISCUSSION The absence of amvlopectin deposition in ,he liver grafts was expected, but (he freedom from neuromus-cular or cardiac morbidity associated with extrahepat-Vol. 324 No. I BRIEF REPORT - SELBY ET AL. 41 A B c D However, there WJ.S little J.mylo-pectin in myocardial-biopsy speci-mens obtained a year or more after liver transplantation. Particularly striking was the decrease in myo-cardial amylopectin over a period of 13 months after liver transplan-tation in Patient 6, whose older brother had minimal heart involve-ment 54 months after transplanta-tion. We speculate that the older brother may have cleared amylo-pectin from his extrahepatic tissues by the time this first heart biopsy was performed. That amylopectin disappears slowly is illustrated by the cases of our patients and may account for unpublished observa-tions in a 14-month-old Belgian child who died of a respiratory in-fection superimposed on congestive heart failure II months "D~fter liver transplantation. Amylopectin was found post mortem in this child's myocardium and in other organs (Otte ]B, University of Louvain Medical School, Brussels: personal communication) . Figure 1. Myocardial Biopsy Specimens from Patient 6 (PAS-D, x40S). These observations could have implications for other enzyme defi-ciencies that affect multiple organs, particularly if cell-to-cell transfer of the deficient enzyme can be dem-onstrated. However, any explana-tion for extrahepatic amylopectin clearance must await a better un-derstanding of the paradoxical en-zymologic features of Type IV gly-cogen storage disease, in which a branching-enzyme defect results in glycogen with fewer than normal branches. 2 Furthermore, the distri-bution of the normal and abnormal branching enzymes may be differ-ent in various tissues. 21 Transverse sections (Panel A) and oblique sections (Panel B) of myocardial fibers in a biopsy specimen obtained 3% weeks after liver transplantation show abundant amylo-pectin inclUSIons (red material). Panels C and D show comparable fields from a biopsy specimen obtained 14 months after transplantation, in which there IS evidence of a Finally, it is possible that long-term cyclosporine therapy was an ameliorating factor in our patients. marked decrease in the number of inclusions. ic amylopectin deposits was more noteworthv. No neuromuscular complications were seen, and the re-tarded growth tha't was characteristic of the patients belore transplantation was restored to more ne<1.rlv normal values in all the survivors. :Viore important, none of the surviving patients has had cJrdiac compli-cations during follow-up periods as long as six vears. Because a wide varietv of ,;ardiac and non cardiac tis-sues collected perioperativelv trom dilferf'11l patient' contained cytopiasmiclmvlopectin. ;1 must he 1, ~umed that ail the patil"nt:; had cardiac ;nvol\"l"lT1t'nl. as \vas demonstratt'd in '.he !cJUr Datients "ttldied. This drug,22 as well as the new immunosuppressive agent .FK 506,23 has hepatotrophic qualities similar to those of insulin,z4 includin~ the ability to increase he-patic glvcogen stores. Both these immunosuppressive drul2;s attach to cvtosolic binding sites that are rich in the ubiquitous enzyme peptidyl-prolyl isomerase/5,26 and both cause wide-ranging immunologic and non-immunologic effects, includin~ alterations in carbohy-drate, cholesterol, and uric acid metabolism.'3 Thus. it is concen'able that the early treatment of patients with f\pe IV glycogen storage disease could obviate the :1eed lor transplantation. 42 THE NEW ENGLAND JOURNAL OF MEDICINE Jan. 3,1991 REFERE:-ICES Anderson DH. Studies on glycDgen disease "vith re?on of :1 case in which the glycogen was abnonna!. In: :--TaJjar V A, ed. Caroohydrate metabolism. Baltimore: Johns Hopkins Press, 1952:28-42. 2. Illingworth B, Cori GT. Structure of glycogens and amylopectins. III. Nor· mal and abnonnal human glycogen. J BioI Chern 1952; 199:653-60. o. Brown BI, Brown DH. Lack of an a·!,4-glucan:a-l,4-g1ucan 6·g1ycosvl transferase in a case of type IV glycogenosis. Proc Natl Acad Sci U S .-\ 1966; 56:725-9. 4. Rannayan GA, Dean WJ, Howell RR. Type IV glycogen-storage disease: light-mIcroscopic, electron-microscopic, and enzymatic study. Am J Clin Pathol 1976; 66:702-9. 5. Greene GM, Weldon DC, Ferrans VJ. et a1. Juvenile polysaccharidosis with cardioskeletal myopathy. Arch Pathol Lab Med 1987; 111:977-82. 6. Hers H·G, Van Hoof F, de Barsy T. Glycogen s[Orage diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D. eds. The metabolic basis of inherited disease. 6th. ed. Vol. I. New York; McGraw-Hill, 1989:425-52. 7. Brown Bl. Debranch.ing and branching enzyme deficiencies. In: Engel AG. Banker BQ, cds, Myology. New York: McGraw-Hi11, 1986:1653·61. 8. Ishihara T, Vchino F. Adachi H, et a1. Type IV glycogenosis - a study of two cases. Acta Pathol Jpn 1975; 25:613·33, 9. Servidei S, Riepe R, Langston C, et a1. Severe cardiopathy in branching enzyme deficiency. J Pediatr [987; 111:51-6. 10. McMaster KR, Powers JM, Hennigar GR Jr. Wohltmann HJ, Farr GH Jr. Nervous system involvement in type IV glycogenosis. Arch Pathol Lab Med 1979; 103: 105·11. I I. Ferguson IT, Mahon M, Cumming WJ. An adult case of Andersen's disease - Type IV glycogenosis: a clinical, histochemical, ultrastructural and bio-chemical srudy. J Neural Sci 1983; 60:337-51. 12. Zellweger H. MueHer S. Ionasescu V, Schoche! SS, McCormick WF. Gly-cogenosis. IV. A new cause of infantile hypotonia. J Pediatr 1972; 80:842· 4. 13. Guerra AS, van Diggelen OP, Carneiro F, Tsou RM. Simoes S, Santos NT. A juvenile variant of glycogenosis IV (Andersen disease). Eur J Pediatr 1986; 145:179-81. [4. Starzl TE. Koep LJ, Halgrimson CO. et a!. Fifteen years of climcal liver transplamation. Gastroenterology 1979; 77:375·88. 15. Brown BI. Brown DH. Branching enzyme activity of cultured amnineytes and chorionic villi: prenatal testing for [ype IV glycogen storage jiseas •. Am J Hum Genet 1989; 44:378-81. 16. Greene HL, Brown BI. McClenathan DT, Agostini RM Jr, Taylor SR. A n'ew variant of Type IV glycogenosis: deficiency of branch.ing enzvme ac· tivity without apparent progressive liver disease. Hepatology 1988: 8:302·6. 17. Starzi TE, Demetris A], Van Thiel D. Liver transplantation. N Engl J Med 1989: 321:1014·22. 18. Ishihara T. Yokota T. Yamashita Y, er al. Comparative study of the intracy-toplasmic inclUSIOns in Lafora disease and type IV glycogenosis by electron microscopy. Acta Pathol Jpn 1987; 37:1591·601. 19. Reed GB Jr. Dixon JFP, Neustein HB, Donnell GN, Landing BH. Type IV glycogenosis: patient with absence of a branching enzyme a-I, 4-glucan: a·l, 4·g1ucan 6-glycosyl transferase. Lab Invest 1968; 19:546·57. 20. Schochet SS Jr, McCormick WF, Zellweger H. Type IV glycogenosis (amy· lopectlnosis): light and electron microscopic observatlons. Arch Pathol 1970; 90:354-63. 21. Brown DH, Brown Bl. Studies of the residual glycogen branching enzyme activity present in human skin fibroblasts from patients with type lV gly-cogen storage disease. Biochem Biophys Res Commun 1983; 1 II :636-43. 22. Mazzaferro V, Porter KA, Scotti-Foglieni CL, et aJ. Th.e hepatotropic effect of cyclosporine. Surgery 1990; 107:533·9. 23. Starz! TE, Porter KA, Mazzaferro V, Todo S, Fung J, Francavilla A. Hepatotrophic effects of FK506 in dogs. Transplantation (in press). 24. Starzl TE, Watanabe K. Porter KA, Putnam CWo Effects of insulin. gluca-gon, and insulin/glucagon infusions on liver morpholog,y and cell division after complete portacaval shunt in dogs. Lancet 1976; 1;,'\21·5. 25. Siekierka JJ, Hurig SHY, Poe M, Lin CS, Sigal NH. A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin. Nature 1989; 341:755-7. 26. Harding MW, Galat A, Uehling DE. Schreiber SL. A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature 1989; 341:758-60. © Copyright, 1991, by the Massachusetts Medical Society Printed in the U.S ,A. THE NEW ENGLAND JOURNAL OF MEDICINE is published weekly in the English language by the Massachusetts Medical Society (Waltham, MA, USA). Material printed in the Journal is covered by copyright. No part of this reprint may be reproduced or transmitted in any form Without written permiSSion. All rights re-served. Direct permiSSion reauests to the Permissions Depart· ment at the USA subscription office. Editorial office: 10 Shattuck Street, Boston, MA 02115, USA. SUBSCRIPTIONS: SUbSCrlD-:ion offices: 1440 Main Street, Waltham, MA 02154-1649, USA; P.O. Box 1123, Commerce Court Postal Station, :oronto, Ontario M5L ~ K1. Canaaa; and Saxon Way, Melbourn. Royston, Herts SG8 6NJ, UK. 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Liver transplantation for type IV glycogen storage disease

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Liver transplantation for type IV glycogen storage disease

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