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Glucose phosphate isomerase deficiency with hereditary nonspherocytic hemolytic anemia
494
October 1974 The Journal o f P E D I A T R I C S
Glucose phosphate isomerase deficiency with hereditary nonspherocytic hemolytic anemia Eight children (5 living, 3 deceased) with severe hereditary nonspherocytic hemolyt& anemia caused by glucose phosphate isomerase defieiency have been observed in two Kentucky and Indiana families. All affected children were severely anemic in early life. Three deaths occurred in young patients who did not receive adequate transfusions of blood or whose parents refused to permit spleneetomy. Spleneetomy generally abolishes the requirement for blood transfusion, No patient has required regular transfusion of blood after puberty. Growth and development have been surprisingly normal and no patient has died of infection. The anemia is expressed as an autosomal recessive trait, but the enzyme variant can be detected in hematologically normal heterozygotes. The abnormal isomerase molecule is heat labile and is contained in neutrophils and lymphocytes as well as in erythroeytes.
John J. Hutton, M.D.,* Lexington, Ky., and Robert R. Chileote, M.D., Indianapolis, Ind.
GLUCOSE PHOSPHATE ISOMERASE deficiency is a rare disorder that results in congenital nonspherocytic hemolytic anemia of varying degrees of severity. Blume and associates 1 recently reported two new patients and alluded to 13 other cases either reported in the literature or known to the investigators. Over the past several years we have identified eight cases of GPI deficiency in two families from Kentucky and Indiana, including the three cases previously reported by Paglia and associates. 2 We report our experience with this relatively large number of patients and point out the generally good prognosis of children who undergo splenectomy early in life.
MATERIALS AND METHODS Venous blood was collected under sterile conditions and anticoagulated with acid-citrate-dextrose, formula From the Department of Medicine, University of Kentucky School of Medicine, and the Department of Pediatrics, Indiana University School of Medicine. Supported by gran ts.from the National Institutes of Health AM-16013 and Research Career Development A ward (Dr. Hutton) 5 K04 AM70186 and by a grant ,from the Riley Memorial Association (Dr. Chilcote). *Reprint address: Department of Medicine, Universityof Kentucky School of Medicine, Lexington, Ky. 40506.
Vol. 85, No. 4, pp. 494-497
A. 3Leukocytes were separated from erythrocytes by repetitive sedimentation of whole blood in 2% dextran. Leukocyte-rich, erythrocyte-poor fractions were layered on an equal volume of Hypaque-Ficoll for centrifugal separation of lymphocytes and granulocytes. 4 Purified erythrocytes were osmotically lysed in Solution G 3, whereas lymphocytes and granulocytes were lysed by freeze-thawing in the same solution. Stromas were removed from lysates by centrifugation at 16,000 g for 10 rain. Abbreviations used GPI: glucosephosphate isomerase Hb: hemoglobin Glycolytic enzymes were assayed at 30~ as described by Beutler, 3 except that in the GPI assay 6-phosphogluconate dehydrogenase was omitted and triethanolamine HC1 buffer, 0.1M final concentration, pH 7.6, was substituted for Tris buffer. Enzyme activities are expressed in units, 1 U being 1 txmole of product formed/rain/gin of Hb. Thermolability of GPI was measured by incubating lysates in Solution G at 50~ and removing aliquots at various times, pH activity curves for GPI were determined in a Tris-glycinephosphate buffer systemS; electrophoretic mobility in
Volume 85 Number 4
Glucose phosphate isomerase deficiency
495
T a b l e I. H e m a t o l o g i c data
Patient L. J. Patient age Hb (gm/100 ml) Total bilirubin (mg/100 ml) Reticulocytes (%) Leukocytes/mm 3 Platelets/mm 3 Coombs' test Autohemolysis (% lysis at 48 hr) Saline Glucose
Patient T. A.
At 2 yr
At 19 yr
At l5 mo
4-5 1.9-4.4 20 12,500 -Neg.
11 5.2 35 12,100 1,010,000 Neg.
5.2 1.5 32 14,500 300,000 Neg.
s t a r c h gel6; M i c h a e l i s ' c o n s t a n t (K m) by dilution o f fruct o s e - 6 - p h o s p h a t e a n d p l o t t i n g o f [S]/V vs. [S].5 E r y t h r o cyte a u t o h e m o l y s i s a n d tests for a b n o r m a l H b were perf o r m e d by s t a n d a r d m e t h o d s . 7
4.8 4.1
i
At lO yr 10 1.3 20 13,000 310,000 Neg.
---
5.4 3.9
IOO to Z
90
80
~5,6
n 3],7
9
~, 36.0
o
9.5
9
9
11,6
~E w
CASE REPORTS Case 1. L. J. had been a term, Caucasian, female infant weighing 9 lb, 8 oz. She was pale at birth, became jaundiced and anemic, and required a blood transfusion at 16 days of age. During her first 2 years of life she received blood transfusions every 4 to 8 weeks because of repeated episodes of hemolysis with jaundice and abdominal pain. Typical hematologic data are given in Table I. Erythrocyte osmotic fragility was normal; no spherocytes were seen on the peripheral blood smear. Splenectomy was performed at 28 mo. After splenectomy her transfusion requirement dramatically decreased to approximately one per year through age 10 yr and she has received none since then except before elective surgery. Growth and development were normal during childhood with her height at the seventy-fifth percentile and weight at Lhe fiftieth. Once or twice per year she has had an episode of crampy abdominal pain associated with nausea and increasing jaundice. Symptoms subside within two or three days following sedation and intravenous fluids. Cholecystectomy for bilirubinate stones was performed without incident at age 19 yr. L. J. is presently a student in college and feels well. Her present hematologic status is summarized in Table I. Her only medication is 1 mg of folate per day. Case 2. T. A., a Caucasian male patient, was born in 1962 and detained in the hospital for one week because he was "not the right color." During the first year of life there were three episodes of irritability, fever, pallor, icterus, and dark urine, but no transfusions of blood were administered. At age 15 mo he was evaluated at Indiana University Medical Center; the hematologic data are summarized in Table I. Physical examination was unremarkable except for mild icterus and extension of the liver 2 cm below the right costal margin. On the peripheral blood smear there were 12 nucleated red blood cells per 100 whit e cells, Howell-Jolly bodies, and occasional spherocytes. The patient received a blood transfusion and therapy was instituted with 1 mg. of folic acid per day. Over the next 15 mo he
'1" 7 0 )-
>- 6 0
3 2 ~'',~
u
,~
4
~ 50 w
~ 40 _z ~ 30
I.z w
o
20
bd
o. I0 O 0
i 15
i 30
i 45
TIME(MINUTES)
i 60 AT 50"C
6 ...___....-..-o i 75
1 90
Fig. 1. Initial activities and thermolability of glucose phosphate isomerase (in ~.mole/gm of Hb/min) in hemolysates from family of patient L. J. Curves 1, 3, and 4 are normal controls. Curve 2, sister V-7 of Fig. 2. Curve 5, father III-8 of Fig. 2. Curve 6, patient L. J., V-9 of Fig. 2. had numerous hemolytic episodes requiring blood transfusion. At age 3 yr his spleen was removed; it was three times normal size. Following splenectomy, the Hb concentration stabilized at approximately 10 gm/100 ml; the reticulocyte count remained in the 20 to 30% range. He has not required transfusion subsequent to the operation. At age 10 yr the patient developed priapism, requiring b u l b o c a v e r n o s u s - t o - b u l b o s p o n g i o s u s shunt. Hematologic data are shown in Table I. Red cell survival (T1/2), determined with the use of 51Cr-labeled cells, is 4 days, with no specific area of increased sequestration. RESULTS
AND
DISCUSSION
B o t h p a t i e n t s h a d n o r m a l h e m o g l o b i n studies. T h e e r y t h r o c y t e a u t o h e m o l y s i s test was a b n o r m a l in e a c h ;
496
Hutton and Chilcote
The Journal of Pediatrics October 1974
TIT
-~
2
I
illl~ IL 2 3
IL 4 5 6 7
6
,AFFECTED
0 NORMAL HETEROZYGOTE~OECEASEO (~) NOT TESTED
Fig. 2. Pedigree of the family of patient L. J.
there was 5% hemolysis at 48 hr, which was not corrected by the addition of glucose. The activities of glycolytic enzymes in the erythrocytes were assayed. The level of GPI was 10-12 U in cells from the two patients, whereas normal control activities ranged from 24-36 U. Activities of the other glycolytic enzymes and glucose-6-phosphate dehydrogenase were either normal or elevated, as would be expected in patients with high reticulocyte counts. None of the properties of GPI from erythrocytes of patient T. A. differed from those of L. J. The isomerase activity in hemolysates from each patient was more rapidly destroyed by heating than normal, with essentially total loss of activity after 15 rain incubation at 50~ (Fig. 1, curve 6). No GPI of normal stability was present. GPI activities in lysates of purified neutrophils and lymphocytes were thermolabile, indicating that these cells also contain the abnormal enzyme. Comparison of GPI activities in hemolysates from normal and defective erythrocytes showed no differences in pH activity curves, in mobility on starch gel electrophoresis, or in affinity (K m) for fructose-6-phosphate. Patients L. J. and T. A. were considered to have congenital nonspherocytic hemolytic anemia secondary to GPI deficiency. The family pedigree of L. J. is shown in Fig. 2, where she is identified as individual V-9. Her parents had normal hematocrits, reticulocyte counts, and peripheral blood smears. However, the activities of erythrocyte GPI in the mother and father were 10.9 and 9.5 U, respectively (normal, 24-36 U). In contrast to patients with GPI deficiency, the parental erythrocytes contained only small amounts of heat-labile isomerase activity; most of the isomerase activity was normally
stable (Fig. 1, curve 5). These data are interpreted to indicate that both parents (Fig. 2, individuals 111-8 and IV-5) are heterozygous carriers of the defective GPI and have differential loss of the labile isomerase activity during the long life span of erythrocytes characteristic of heterozygotes. 8 Sib V-3 (Fig. 2) was a term female infant who became jaundiced on the second day of life, began bleeding on the tenth day, and died at 11 days of age. Sib V-4 was a term male infant who had episodes of jaundice, anemia, and vomiting during early life. He died of jaundice and anemia at 7 yr of age. Splenectomy had been recommended, but the family refused. Sib V-5 died at 8 mo; he had anemia and jaundice, it seems clear from the clinical histories that each of these sibs was afflicted with GPI deficiency. The parents of these children are first cousins once removed and were born in southeastern Kentucky. After extensive family studies, it was found that patient L. J. (V-9) is related to the family with G P I deficiency reported by Paglia and associates. 2 Generation VI individuals 1 to 7 (Fig. 2) correspond to generation III individuals 1 to 7 in Paglia's figure 1. A blood sample was obtained from individual VI-2 through the courtesy of Dr. Phillip Holland. The GPI in her ceils could not be distinguished from that of patient L. J. Individuals VI-2, VI-3, and VI-7 range from 8-19 yr of age; they had splenectomies early in life. Both parents of our patient T. A. were born in northeastern Kentucky and are carried of the defective GPI. They are not known to be related to any member of the pedigree shown in Fig. 2. Because of the limited geographic area from which this cluster of cases of GPI deficiency comes, proved consanguinity in one family, and the biochemical simi-
Volume 85 Number 4
larity of the defective enzyme in all patients, it is highly probable that all of the affected individuals are homozygous for a single, specific isomerase deficiency allele, which we call the " K e n t u c k y v a r i a n t . " I n d i v i d u a l s homozygous for the "Kentucky variant" are ill from birth and usually require transfusion within the first two weeks of life. Splenectomy has been performed on all living patients within the first 3 yr o f life, and in all of them blood transfusion requirements have been dramatically decreased or eliminated after operation. Continuing hemolysis increases bone marrow demands for folic acid, so that all p a t i e n t s receive s u p p l e m e n t a l folate, 1 mg/day. Treatment with oral iron is detrimental unless iron deficiency is clearly demonstrated. Because of chronic administration of oral iron for "anemia," one of our patients has marked bone marrow hemosiderosis. P a t i e n t s with G P I deficiency require careful m e d i c a l management throughout childhood. However, with such management they can lead relatively normal lives and can be expected to grow and develop normally. We thank Drs. Phillip Holland and Robert L. Baehner for assistance.
REFERENCE'S 1. Blume, K. G., Hryniuk, W., Powars, D., Trinidad, F., West, C., and Beutler, E.: Characterization of two new
Glucose phosphate isomerase defic&ncy
2.
3. 4.
5.
6.
7.
8.
497
variants of glucose phosphate isomerase deficiency with hereditary nonspherocytic hemolytic anemia, J. Lab. Clin. Med. 79: 942, 1972. Paglia, D. E., Holland, P., Baughan, M. A., and Valentine, W. N.: Occurrence of defective hexose phosphate isomerization in human erythrocytes and leukocytes, N. Engl. J. Med. 280: 66, 1969. Beutler, E.: Red cell metabolism: A manual of biochemical methods, New York, 1971, Grune & Stratton, Inc. Thorsky, E.: Cell specific and common antigens on human granulocytes and lymphocytes demonstrated with cytotoxic heteroantibodies, Vox Sang. 13: 194, 1967. Beutler, E., Mathai, C. K., and Smith, J. E.: Biochemical variants of glucose-6-phosphate dehydrogenase giving rise to congenital nonspherocytic hemolytic disease, Blood 31: 131, 1968. Detter, J. C., Ways, P. O., Giblett, E. R., Baughan, M. A., Hopkinson, D. A., Povey, S., and Harris, H.: Inherited variation in human phosphohexose isomerase, Ann. Hum. Genet. 31: 329, 1968. Williams, W. J., Beutler, E., Erslev, A., and Rundles, R. W., editors: Hematology, New York, 1971, McGraw Hill Book Company, Inc. Arnold, H., Blume, K., Engelhardt, R., and Lohr, G. W.: Glucose phosphate isomerase deficiency: Evidence for in vivo instability of an enzyme variant with hemolysis, Blood 41: 691, 1973.
October 1974 The Journal o f P E D I A T R I C S
Glucose phosphate isomerase deficiency with hereditary nonspherocytic hemolytic anemia Eight children (5 living, 3 deceased) with severe hereditary nonspherocytic hemolyt& anemia caused by glucose phosphate isomerase defieiency have been observed in two Kentucky and Indiana families. All affected children were severely anemic in early life. Three deaths occurred in young patients who did not receive adequate transfusions of blood or whose parents refused to permit spleneetomy. Spleneetomy generally abolishes the requirement for blood transfusion, No patient has required regular transfusion of blood after puberty. Growth and development have been surprisingly normal and no patient has died of infection. The anemia is expressed as an autosomal recessive trait, but the enzyme variant can be detected in hematologically normal heterozygotes. The abnormal isomerase molecule is heat labile and is contained in neutrophils and lymphocytes as well as in erythroeytes.
John J. Hutton, M.D.,* Lexington, Ky., and Robert R. Chileote, M.D., Indianapolis, Ind.
GLUCOSE PHOSPHATE ISOMERASE deficiency is a rare disorder that results in congenital nonspherocytic hemolytic anemia of varying degrees of severity. Blume and associates 1 recently reported two new patients and alluded to 13 other cases either reported in the literature or known to the investigators. Over the past several years we have identified eight cases of GPI deficiency in two families from Kentucky and Indiana, including the three cases previously reported by Paglia and associates. 2 We report our experience with this relatively large number of patients and point out the generally good prognosis of children who undergo splenectomy early in life.
MATERIALS AND METHODS Venous blood was collected under sterile conditions and anticoagulated with acid-citrate-dextrose, formula From the Department of Medicine, University of Kentucky School of Medicine, and the Department of Pediatrics, Indiana University School of Medicine. Supported by gran ts.from the National Institutes of Health AM-16013 and Research Career Development A ward (Dr. Hutton) 5 K04 AM70186 and by a grant ,from the Riley Memorial Association (Dr. Chilcote). *Reprint address: Department of Medicine, Universityof Kentucky School of Medicine, Lexington, Ky. 40506.
Vol. 85, No. 4, pp. 494-497
A. 3Leukocytes were separated from erythrocytes by repetitive sedimentation of whole blood in 2% dextran. Leukocyte-rich, erythrocyte-poor fractions were layered on an equal volume of Hypaque-Ficoll for centrifugal separation of lymphocytes and granulocytes. 4 Purified erythrocytes were osmotically lysed in Solution G 3, whereas lymphocytes and granulocytes were lysed by freeze-thawing in the same solution. Stromas were removed from lysates by centrifugation at 16,000 g for 10 rain. Abbreviations used GPI: glucosephosphate isomerase Hb: hemoglobin Glycolytic enzymes were assayed at 30~ as described by Beutler, 3 except that in the GPI assay 6-phosphogluconate dehydrogenase was omitted and triethanolamine HC1 buffer, 0.1M final concentration, pH 7.6, was substituted for Tris buffer. Enzyme activities are expressed in units, 1 U being 1 txmole of product formed/rain/gin of Hb. Thermolability of GPI was measured by incubating lysates in Solution G at 50~ and removing aliquots at various times, pH activity curves for GPI were determined in a Tris-glycinephosphate buffer systemS; electrophoretic mobility in
Volume 85 Number 4
Glucose phosphate isomerase deficiency
495
T a b l e I. H e m a t o l o g i c data
Patient L. J. Patient age Hb (gm/100 ml) Total bilirubin (mg/100 ml) Reticulocytes (%) Leukocytes/mm 3 Platelets/mm 3 Coombs' test Autohemolysis (% lysis at 48 hr) Saline Glucose
Patient T. A.
At 2 yr
At 19 yr
At l5 mo
4-5 1.9-4.4 20 12,500 -Neg.
11 5.2 35 12,100 1,010,000 Neg.
5.2 1.5 32 14,500 300,000 Neg.
s t a r c h gel6; M i c h a e l i s ' c o n s t a n t (K m) by dilution o f fruct o s e - 6 - p h o s p h a t e a n d p l o t t i n g o f [S]/V vs. [S].5 E r y t h r o cyte a u t o h e m o l y s i s a n d tests for a b n o r m a l H b were perf o r m e d by s t a n d a r d m e t h o d s . 7
4.8 4.1
i
At lO yr 10 1.3 20 13,000 310,000 Neg.
---
5.4 3.9
IOO to Z
90
80
~5,6
n 3],7
9
~, 36.0
o
9.5
9
9
11,6
~E w
CASE REPORTS Case 1. L. J. had been a term, Caucasian, female infant weighing 9 lb, 8 oz. She was pale at birth, became jaundiced and anemic, and required a blood transfusion at 16 days of age. During her first 2 years of life she received blood transfusions every 4 to 8 weeks because of repeated episodes of hemolysis with jaundice and abdominal pain. Typical hematologic data are given in Table I. Erythrocyte osmotic fragility was normal; no spherocytes were seen on the peripheral blood smear. Splenectomy was performed at 28 mo. After splenectomy her transfusion requirement dramatically decreased to approximately one per year through age 10 yr and she has received none since then except before elective surgery. Growth and development were normal during childhood with her height at the seventy-fifth percentile and weight at Lhe fiftieth. Once or twice per year she has had an episode of crampy abdominal pain associated with nausea and increasing jaundice. Symptoms subside within two or three days following sedation and intravenous fluids. Cholecystectomy for bilirubinate stones was performed without incident at age 19 yr. L. J. is presently a student in college and feels well. Her present hematologic status is summarized in Table I. Her only medication is 1 mg of folate per day. Case 2. T. A., a Caucasian male patient, was born in 1962 and detained in the hospital for one week because he was "not the right color." During the first year of life there were three episodes of irritability, fever, pallor, icterus, and dark urine, but no transfusions of blood were administered. At age 15 mo he was evaluated at Indiana University Medical Center; the hematologic data are summarized in Table I. Physical examination was unremarkable except for mild icterus and extension of the liver 2 cm below the right costal margin. On the peripheral blood smear there were 12 nucleated red blood cells per 100 whit e cells, Howell-Jolly bodies, and occasional spherocytes. The patient received a blood transfusion and therapy was instituted with 1 mg. of folic acid per day. Over the next 15 mo he
'1" 7 0 )-
>- 6 0
3 2 ~'',~
u
,~
4
~ 50 w
~ 40 _z ~ 30
I.z w
o
20
bd
o. I0 O 0
i 15
i 30
i 45
TIME(MINUTES)
i 60 AT 50"C
6 ...___....-..-o i 75
1 90
Fig. 1. Initial activities and thermolability of glucose phosphate isomerase (in ~.mole/gm of Hb/min) in hemolysates from family of patient L. J. Curves 1, 3, and 4 are normal controls. Curve 2, sister V-7 of Fig. 2. Curve 5, father III-8 of Fig. 2. Curve 6, patient L. J., V-9 of Fig. 2. had numerous hemolytic episodes requiring blood transfusion. At age 3 yr his spleen was removed; it was three times normal size. Following splenectomy, the Hb concentration stabilized at approximately 10 gm/100 ml; the reticulocyte count remained in the 20 to 30% range. He has not required transfusion subsequent to the operation. At age 10 yr the patient developed priapism, requiring b u l b o c a v e r n o s u s - t o - b u l b o s p o n g i o s u s shunt. Hematologic data are shown in Table I. Red cell survival (T1/2), determined with the use of 51Cr-labeled cells, is 4 days, with no specific area of increased sequestration. RESULTS
AND
DISCUSSION
B o t h p a t i e n t s h a d n o r m a l h e m o g l o b i n studies. T h e e r y t h r o c y t e a u t o h e m o l y s i s test was a b n o r m a l in e a c h ;
496
Hutton and Chilcote
The Journal of Pediatrics October 1974
TIT
-~
2
I
illl~ IL 2 3
IL 4 5 6 7
6
,AFFECTED
0 NORMAL HETEROZYGOTE~OECEASEO (~) NOT TESTED
Fig. 2. Pedigree of the family of patient L. J.
there was 5% hemolysis at 48 hr, which was not corrected by the addition of glucose. The activities of glycolytic enzymes in the erythrocytes were assayed. The level of GPI was 10-12 U in cells from the two patients, whereas normal control activities ranged from 24-36 U. Activities of the other glycolytic enzymes and glucose-6-phosphate dehydrogenase were either normal or elevated, as would be expected in patients with high reticulocyte counts. None of the properties of GPI from erythrocytes of patient T. A. differed from those of L. J. The isomerase activity in hemolysates from each patient was more rapidly destroyed by heating than normal, with essentially total loss of activity after 15 rain incubation at 50~ (Fig. 1, curve 6). No GPI of normal stability was present. GPI activities in lysates of purified neutrophils and lymphocytes were thermolabile, indicating that these cells also contain the abnormal enzyme. Comparison of GPI activities in hemolysates from normal and defective erythrocytes showed no differences in pH activity curves, in mobility on starch gel electrophoresis, or in affinity (K m) for fructose-6-phosphate. Patients L. J. and T. A. were considered to have congenital nonspherocytic hemolytic anemia secondary to GPI deficiency. The family pedigree of L. J. is shown in Fig. 2, where she is identified as individual V-9. Her parents had normal hematocrits, reticulocyte counts, and peripheral blood smears. However, the activities of erythrocyte GPI in the mother and father were 10.9 and 9.5 U, respectively (normal, 24-36 U). In contrast to patients with GPI deficiency, the parental erythrocytes contained only small amounts of heat-labile isomerase activity; most of the isomerase activity was normally
stable (Fig. 1, curve 5). These data are interpreted to indicate that both parents (Fig. 2, individuals 111-8 and IV-5) are heterozygous carriers of the defective GPI and have differential loss of the labile isomerase activity during the long life span of erythrocytes characteristic of heterozygotes. 8 Sib V-3 (Fig. 2) was a term female infant who became jaundiced on the second day of life, began bleeding on the tenth day, and died at 11 days of age. Sib V-4 was a term male infant who had episodes of jaundice, anemia, and vomiting during early life. He died of jaundice and anemia at 7 yr of age. Splenectomy had been recommended, but the family refused. Sib V-5 died at 8 mo; he had anemia and jaundice, it seems clear from the clinical histories that each of these sibs was afflicted with GPI deficiency. The parents of these children are first cousins once removed and were born in southeastern Kentucky. After extensive family studies, it was found that patient L. J. (V-9) is related to the family with G P I deficiency reported by Paglia and associates. 2 Generation VI individuals 1 to 7 (Fig. 2) correspond to generation III individuals 1 to 7 in Paglia's figure 1. A blood sample was obtained from individual VI-2 through the courtesy of Dr. Phillip Holland. The GPI in her ceils could not be distinguished from that of patient L. J. Individuals VI-2, VI-3, and VI-7 range from 8-19 yr of age; they had splenectomies early in life. Both parents of our patient T. A. were born in northeastern Kentucky and are carried of the defective GPI. They are not known to be related to any member of the pedigree shown in Fig. 2. Because of the limited geographic area from which this cluster of cases of GPI deficiency comes, proved consanguinity in one family, and the biochemical simi-
Volume 85 Number 4
larity of the defective enzyme in all patients, it is highly probable that all of the affected individuals are homozygous for a single, specific isomerase deficiency allele, which we call the " K e n t u c k y v a r i a n t . " I n d i v i d u a l s homozygous for the "Kentucky variant" are ill from birth and usually require transfusion within the first two weeks of life. Splenectomy has been performed on all living patients within the first 3 yr o f life, and in all of them blood transfusion requirements have been dramatically decreased or eliminated after operation. Continuing hemolysis increases bone marrow demands for folic acid, so that all p a t i e n t s receive s u p p l e m e n t a l folate, 1 mg/day. Treatment with oral iron is detrimental unless iron deficiency is clearly demonstrated. Because of chronic administration of oral iron for "anemia," one of our patients has marked bone marrow hemosiderosis. P a t i e n t s with G P I deficiency require careful m e d i c a l management throughout childhood. However, with such management they can lead relatively normal lives and can be expected to grow and develop normally. We thank Drs. Phillip Holland and Robert L. Baehner for assistance.
REFERENCE'S 1. Blume, K. G., Hryniuk, W., Powars, D., Trinidad, F., West, C., and Beutler, E.: Characterization of two new
Glucose phosphate isomerase defic&ncy
2.
3. 4.
5.
6.
7.
8.
497
variants of glucose phosphate isomerase deficiency with hereditary nonspherocytic hemolytic anemia, J. Lab. Clin. Med. 79: 942, 1972. Paglia, D. E., Holland, P., Baughan, M. A., and Valentine, W. N.: Occurrence of defective hexose phosphate isomerization in human erythrocytes and leukocytes, N. Engl. J. Med. 280: 66, 1969. Beutler, E.: Red cell metabolism: A manual of biochemical methods, New York, 1971, Grune & Stratton, Inc. Thorsky, E.: Cell specific and common antigens on human granulocytes and lymphocytes demonstrated with cytotoxic heteroantibodies, Vox Sang. 13: 194, 1967. Beutler, E., Mathai, C. K., and Smith, J. E.: Biochemical variants of glucose-6-phosphate dehydrogenase giving rise to congenital nonspherocytic hemolytic disease, Blood 31: 131, 1968. Detter, J. C., Ways, P. O., Giblett, E. R., Baughan, M. A., Hopkinson, D. A., Povey, S., and Harris, H.: Inherited variation in human phosphohexose isomerase, Ann. Hum. Genet. 31: 329, 1968. Williams, W. J., Beutler, E., Erslev, A., and Rundles, R. W., editors: Hematology, New York, 1971, McGraw Hill Book Company, Inc. Arnold, H., Blume, K., Engelhardt, R., and Lohr, G. W.: Glucose phosphate isomerase deficiency: Evidence for in vivo instability of an enzyme variant with hemolysis, Blood 41: 691, 1973.