Glycogen storage disease

Glycogen Storage Disease* Biochemical and Clinical Data in Sixteen Cases S. VAN CREVELD, M .D . and F . HUIJING, Amsterdam, The Netherlands N

the last few years we have observed, in

genosis (Pompe's disease) [3], glycogen accumulates in all the tissues . In the majority of patients the heart is greatly enlarged but there is no murmur . Sometimes the patient has macroglossia and muscle hypotonia or an enlarged liver . Rarely, the extreme hypotonia is accompanied by neurologic symptoms (neuromuscular form of the disease) . Characteristic deviations in the electrocardiogram are a constant feature in these cases . The life span of these patients is limited, usually not more than a year . Blood sugar values and glycolytic metabolism are normal . In some cases of acid a-glucosidase deficiency enlargement of the heart is not a prominent feature, but the clinical picture is dominated by a marked muscle hypotonia, with or without enlargement of the liver [4, .5] . In debranching enzyme deficiency the dominating feature is enlargement of the liver, with occasional attacks of hypoglycemia, as a rule accompanied by ketosis . Sometimes the lipid content of the blood is increased . The blood sugar level usually does not drop as low as in glucose 6-phosphatase deficiency (type I) . There is a deficiency of debranching enzyme in the liver [6], erythrocytes [7,81 and leukocytes [7,9,101, with or without a deficiency in skeletal and heart muscles [11] . The glycogen in these patients has an abnormal structure and the concentration in the blood is increased, partly due to the increased glycogen content of the erythrocytes [ 12], but mainly to the accumulation of glycogen in the leukocytes . The prognosis is favorable . In our patients who have reached puberty the liver is no longer enlarged [5] . In the glycogen disease caused by the partial deficiency of liver phosphorylase [13], enlargement of the liver is also characteristic . Although at times there is no hypoglycemia in the fasting condition, moderate hypoglycemia is generally present .

I addition to the two patients with glycogen disease which we have followed for many years, fourteen new cases of this disease . This is a report of our experiences with these patients . Classified according to the enzyme deficiency causing the disease, we found two patients with glucose 6-phosphatase deficiency (type i glycogenosis), one patient with acid a-glucosidase deficiency (type it), nine patients with debranching enzyme deficiency (type in) and four with liver phosphorylase deficiency (type vi) . Glucose 6-phosphatase, the enzyme which hydrolyses glucose 6-phosphate into glucose and phosphate, is normally present in the liver, kidney and small intestine [7] . When it is not present in normal amounts, the liver is greatly enlarged and contains large amounts of glycogen, often more than 10 per cent of the wet weight, and very often also large amounts of fat . Enlargement of the liver is sometimes present even at birth, but is generally only noticed after a few months . The kidneys are often also enlarged . Usually there is associated fasting hypoglycemia accompanied by high blood lactate levels and, very often, ketosis . In many cases hyperlipemia is present, whereas in others high levels of uric acid are found, with or without symptoms of gout . The low blood sugar concentration and the acidosis sometimes cause convulsions, but not as often as expected, as lactate can be used as a fuel for the brain . Growth is stunted . The patients are incapable of converting galactose and fructose into glucose, but they convert these sugars into lactate . Acid a-glucosidase hydrolyses terminal a-1,4 glucosidic linkages, such as occur in glycogen or maltose, at low pH [2] . It is a so-called --amylase. When the enzyme is present in insufficient amounts, as is the case in generalized glyco"From the Pediatric Clinic and the Laboratory Netherlands. Manuscript received April 1, 1964 .

PH .D .

of

Physiological Chemistry . University

554

of

Amsterdam, The

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TABLE I

care N

Fttear

C:uuveniun of lv nuee

Sex and Age

Acid Deb ranching, I'ItosphurvlEnzyme Leukocyte * Lrukuc yte s t

Ptuents

F. R. E T.

M, 2 F, 40

L acta te Laaatc

0 .43

'd

n-l stein eb ko s,

r care-&P Yh tan 15 .8 17 .0

1

mare . .. F,", in Pl asma ClnBl d (1 5 , (, c r t

t

SCOT (mtnl

dernm I "cute Ihh drc-

~GPT a

ty

c=c

Ytdl

D fzinuy

4 .4

42 68

9 .1 10 .8

PaHrvt mi
t,-1

A. v

0 .17

v, 34

15-3

0_04

1,730

Patients with Deheamhiag Enzyme D ejldrnev u,_t n,-2 n:-3 itt-4 uo-5 to-6

x . Ba . A LM- S L R . -A . Elk, A . D. .l . Z . P . Le . D . L .e .

n -S nt-9

r, 40 M, 42 F, 39 F. 4 F, 2 C, 2 F, 3 F, 6 F, 5

Glucose 0 .00 Glucose 0 .00 Glucose 0 00 Clucuse Glucose 0 .00 Glucose 0 .00 Glucose 0_00 Glucose 0_00 Glucose 0 .00

17 .6 20 .1 23 .6 >12 16 .8 15 .6 16 .2 23 .5 17 .6

0

17 .5 18 .9 14 .7 17 .0 35 .5

310 890 520 610 265 515

1

9 55

213 330

335 170 880 280 375

635 630 I,6'90 l

Patent : amth Doer Pimrpho .y7are D fri

Zvt-1 ct-2 ,,-3 's-4

1'- CI . G1,6 . CL O . .S . S . I

Norm :d

M, 3

M .4 M, 13 M, 14

I-

-

Glucose Glucose Glucose

0 .15 0 .42 0 .24 0 .40

Gwenee

0 .15-0 .50

6 7 08 6 .8 0 .0 1240

8 .2 0

0 .6 3 .6

5-25

5-10

35 43 180 12

25 94 10

840

5-35

630 630 354 185 300-300

* Millimicromoles glucose produced from"phosphorylase limit dextrin" per minute per milligram leukucyIF extract protein . f Millimicrmuolet glucose . .phosphate formed by phosphorolysis of glyeogen . . .. luhlc starch per minure per milligram leukocyte extract prolein . I Millimicrumolet malmse hydrolysed to glucose per minme per milligram leukocyte extract protein (the activity Is measured in a crude leukocyte l umogenzte) .

Enzyme activity is diminished not only in the liver but also in the leukocytes [14,75] . The prognosis is favorable . METHODS

The total blood sugar content was determined by the method of Folin and Wu, and the true glucose content of the blood with the glucose-oxidase method [76] . Blood lactate was determined in trichloroacetic acid extracts of blood or plasma with lactate dehydrogenase, in principle as described by Hohorst [17] . The cholesterol level was estimated with the Liebermann-Burchardt reaction in Bloor's extract . Lipid phosphorus was measured in the same extract . Serum triglyceride levels were determined according to the method of Connerty et al . [18] . Serum uric acid was determined according to the method of Folin with the modification of de Vries and van Daatselaar [19] . The glycogen content was estimated in a trichloroacetic acid extract of total blood or erythrocytes after double precipitation with alcohol, with the anthron method [20] . The glucagon test was performed by intravenous voI . .

38, APRIL 1965

injection of 0 .7 mg, per Mx . body surface area ; after this injection the blood sugar content was followed for 40 minutes . In the epinephrine test; the blood sugar content was followed for 30 minutes after the subcutaneous injection of 0 .25 mg . of epinephrine . The intravenous galactose test was performed according to the method of Schwartz et al . 127] . Serum glutamic oxaloacetic and serum glutamic pyruvic transaminase (SGOT and SGPT) levels were determined in a number of patients using the color test with p-nitrophenylhydrazine . Lactate dehydrogenase in plasma was determined spectrophotometrically . The phosphorylase in leukocytes was determined, in principle, as indicated by Hulsmann et al . [14], with the modification of Huijing [70] . The amount of debranching enzyme in leukocytes was determined according to the method of Huijing [10] . Acid alphaglucosidase was measured according to the method of Hers [71] . CASE REPORTS

In 'Fable 1 are summarized the data obtained in the different patients . It appears that two



556

Glycogen Storage Disease-van Creveld, Huijing

m9 . %

Saccl,o,are I .5 pm ./,p . o,,Il y - 91ocd Sugar

140

----TI . .

Gwr . .

140 Acid 120

N . .ne1 Cantroi 5,6j-,

P .,ien, F . B . Born October 6, 1961

BC

Glycogen Di,ea,e, Type I

- -------- ----

60

4U

20

75

9o

105

120

135

150 sTe .

FIG . 1 . Comparison of changes in total blood sugar, true glucose and lactic acid after oral administration to normal subject (right) and to patient with glycogen storage disease type I (left), of saccharose 1 .5 gm . per kg .

patients (i-1 and t-2) are characterized by an abnormal galactose test, high lactic acid levels in fasting blood, normal amounts of debranching enzyme in leukocytes in one of the two pa-

and acid alpha-glucosidase activity in leukocytes was normal . The phosphorylase activity of the leukocytes was decreased in all these patients . Previously, in the only patient in whom a

tients (no determination could be made in the other), normal phosphorylase levels in leukocytes, and normal amounts of glycogen in the blood .

biopsy of the liver was performed,. the liver was deficient in this enzyme . The history of each case will now be discussed .

One patient (n-1) showed a deficiency of alpha-glucosidase in the leukocytes, while leukocyte phosphorylase and debranching enzyme activity were normal, as was the transformation of galactose into glucose 123] . The Schwartz test was performed in seven of the nine patients with deficiency of debranching enzyme . Normally, all these patients could convert galactose into glucose . In eight patients there was a complete absence of the debranching enzyme in the leukocytes . The amount of phosphorylase in leukocytes was determined in all nine patients and found to be normal . One patient died and, at autopsy (Prof. Hers), specimens of the liver and heart demonstrated the absence of the debranching enzyme . In six of the nine patients, the acid alphaglucosidase in the leukocytes was determined and found to be present in normal amounts . Blood glycogen was determined in six patients and found to be increased . In two patients liver tissue was also examined and found to be deficient in debranching enzyme . In four patients with glycogen liver disease there was a normal conversion of galactose into glucose, and the amount of debranching enzyme

F-1 . Our first patient with glucose 6-phosphatase deficiency was a male infant admitted to the Paediatric Clinic at the age of three months because of a large liver and convulsions . He was the second child of a second marriage of the mother . From the first marriage she had another child . The other two children were boys in good health . There is no consanguinity between parents and grandparents of the patient. Our patient was born at home, spontaneously and at term ; his birthweight was 3,625 gm_ He had not been asphyctic at birth . About 20 hours after birth he became progressively icteric and dull . On the fifth day of life he was admitted to a hospital . He was then ill, dehydrated and slightly anemic . The liver was palpable 3 fingers below the costal margin . The bilirubin content of the scrum was 18 .3 mg . per cent, of which 8 .7 mg . per cent was directly reacting . A day later these values were, respectively, 33 .2 and 21 .8 mg . per cent. There was no blood-group antagonism between mother and child . The Coombs' test result was negative . The urine contained bilirubin and urohilinogen . The sediment was normal . As the general condition was bad and the bilirubin content of the serum increased, although only partly due to an increase of the indirect bilirubin, an exchange transfusion with. 500 ml . heparinized blood was performed on the seventh day of life . After that the serum bilirubin content decreased and the icterus disap . AMERICAN

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Glycogen Storage Disease -ran Crec ;eld, Hui in,; Feared rapidly . Toxoplasmosis, cytomegalic inclusion disease and syphilis were excluded . On the eleventh day of life the fasting blood sugar content proved to be very low (13 mg . per 100 ml .) . At the age of six weeks the infant was discharged . Four weeks later he had his first Convulsion, which recurred several times in the course of one day . Admission to the hospital followed and some days later he was transferred to the Children's Clinic, by Dr . Bockwinkcl (Delft) . 'I his patient is now over two years old . He is still fed every 3 hours with a feeding containing mainly glucose or a polymer of this carbohydrate . He is not given any fructose and only a small amount of galactose, because neither can be converted into glucose . In Figure 1 it can be seen that after tire administration of saccharose the lactic acid content of the blood increased, but the increase in the true glucose concentration was far less than could be expected after the administration of glucose alone . Moreover, the glucose concentration of the blood decreased rapidly to an extremely low value . The impression was that the simultaneous presence of glucose and fructose considerably accelerated glucose consumption . The threatening hypoglycemic attacks can always be prevented or terminated by frequent use of glucose . The patients general condition is excellent . The liver is now somewhat smaller . Mental development is normal. Recently we have been able to give him the necessary quantity of milk in the form of lactose-poor milk,* which caused a slight improvement in his condition . Some time ago the patient had a thrush infectionn in the mouth, which has now disappeared . About Iwo years ago a small adenoid was removed because of recurrent otitis media, Since then the patient has remained well and no increased susceptibility to infections has been noted . There is no tendency for hemorrhages . The development of the bones of the wrists has not been retarded in relation to age . t-2 . Our second patient with glucose 6-phosphatase deficiency has been described in detail elsewhere ; in association with Brombacher et al . 122] . She is now forty-one years old . Her liver was large at birth and is still very much enlarged . She does not exhibit any particular symptoms, except gout . She has one child, who is in good health and free of enlargement of the liver . u-1 . We have seen one case of generalized glycogenosis in recent years, thanks to the friendly collaboration of Dr . Vaandrager (Gouda) . This child was described in detail elsewhere [23], at which time the possibility of making a diagnosis by the investigation of leukocytes was pointed out for alpha-glucnsidase proved to be deficient not only in the heart muscle and * Thanks are due to "De Friese Vlag" Condensed Milk factory, Leeuwarden for the preparation of this milk which contains less than I per cent of lactose . VOL . 38, APRIL 1 96 3

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other o rgans . as was found by Hers 11j . but also in leukocytes . Since this report our patient has died and the deficiency was demonstrated in the brat t muscle, liver and striated muscles . iii-I and 2 . We have seen nine patients wide d( branching enzyme deficiency (type in) . [lie elder two (i and 2) are now respectively forty-nvo and forty years old and have been described repeatedly [51 ; the latest report appeared in ,Aletah ;li,nt [21~ . After reaching puberty the size of the dicer gradually decreased in both patients . m-3 . The description of this adult female patient was given with Brombacher et al . [77 ; . t he results of the laboratory studies it) this patient are, summarized in [able r . at-4 . This girl was referred to its by Dr, van Zeben from the Juliana Children's Hospital at The . Hague and examined in our clinic for the first time at the age of four years . Her weight was then 12 .07 kg ., height 87 cur . She had a very large liver and xanthomas of the skin in several places, especially in the skinfolds . The cholesterol content of the serum at the first investigation was 1,298 mg . per cent. 'I he electrocardiogram showed no deviations . At subsequent examinations even higher values for cholesterol were found, once 1,690 mg, per cent, Attempts to influence this high cholesterol level by diet or medicaments have had no success . Based on the normal result of the intravenous galactose test . the normal phosphorylase activity of the leukocytes, and the increased glycogen content of blood and erythrocytes (ciz . Table rl . we concluded that this patient was suffering from debranching enzyme deficiency . At the age of five and a half years the patient died, after having had symptoms showing cerebral involvement for several days . Autopsy was performed 4 hours after death in the pathological laboratory of the neurological and neurosurgical clinic St . Ursula at Wassenaar . 'the results of the autopsy were kindly put at our disposal by Prof. Wijers and Dr . A- C . de Vet . The weight of the brain was 1,250 gm ., of the heart 95 gm ., of the liver 2,500 gm ., whereas the weight of each kidney was 60 gm . In the right cerebral hemisphere a large tumor was found which, on microscopic investigation, turned out to be an astrocytoma, grade iv (glioblastoma multiform-type) . '[he liver cells were enormously enlarged and partly filled viii a substance which gave positive reaction to periodic acidSchiff base staining . Saliva-amylase caused complete disappearance of this substance from the liver cells . Glycogen determination in the liver gave a value of 14 per cent of the wet weight . In the deeper layers of the heart the muscle fibers showed marked vacuolization, the vacuoles being partly filled with a substance which gave a positive reaction to periodic acidSchiff staining . This substance also disappeared completely after treatment with saliva-amylase . The



558

Glycogen Storage Disease-van Creaeld, Huijing

glycogen content of the heart was 4 .9 per cent . In the kidney the cells of Henle's loop contained a substance which gave a positive reaction to periodic acid-Schiff staining, and completely disappeared after treatment with saliva-amylase . Material which gave a strong positive reaction to periodic acid-Schiff staining was found also in the nonstriated muscle fibers of the bronchi . Striated muscle fibers from different places appeared very atrophic, and judged by the periodic acid-Schiff stain, contained little glycogen, which disappeared completely after treatment with saliva-amylase . In the lumbar part of the spinal cord there was a notable number of very large ganglion cells . Judged by the periodic acid-Schiff stain, they contained little glycogen, which disappeared completely after treatment with amylase . Much glycogen, therefore, was found in this case in the liver, and some also in the heart, muscle fibers, cells of Henle's loop and ganglion cells of the spinal cord . The structure of the glycogen in the liver and heart was found by Prof. Hers to be abnormal, resembling that of a limit dextrin . This corresponded with the absence of debranching enzyme in liver and heart . The cause of death was a brain tumor . in-5 . This girl, the younger sister of two children, is now three years old . She was born spontaneously at term . The father and mother are first cousins . At the age of several months the diagnosis of congenital toxoplasmosis was made, based on slight abnormalities in the fundus oculi, but especially on the serologic reactions (Sabin-Feldman test 1 : 4096 positive, complement fixation test 1 :32 positive) . Shortly after birth she was found to have an enormously enlarged liver with a clearly palpable incisure . Spleen and kidneys were not palpable . The tone of the muscles presently is weak . In the fasting urine the reaction for acetone is positive ; the fasting blood sugar concentration is low . A biopsy of the liver had been performed elsewhere and the diagnosis of hepatomegalia glycogenica made . From biochemical tests and enzyme determinations in leukocytes (and in erythrocytes by Prof . Hers) we concluded that the patient has a deficiency of debranching enzyme. In the morning after an overnight fast, this girl often had attacks of hypoglycemia, which disappeared immediately after prescription of a protein-rich meal at night . This treatment had been advised previously for glycogen disease in general [251, but in our experience proved to be successful only in debranching enzyme deficiency . nt-6 . This female patient had been admitted by Dr . Bartels (Weert) to the Paediatric Clinic for observation at the age of seventeen months . She was the first child of healthy parents, of whom no consanguinity was known . The child was born spontaneously, without cyanosis, at term ; her birth weight was 3,350 gr . She has always had a protruding abdomen in which an enormously enlarged liver

could be palpated ; the spleen has not been enlarged . There was no reducing substance or acetone in the urine . A urobilin test in the urine was slightly positive . An iontophoretic test was performed because of profuse perspiration, but there was no increase in the excretion of electrolytes [26,27] . A biopsy specimen of the liver showed it to be rich in glycogen, with slight cirrhosis. The liver had a grey-yellow color . The spleen was not enlarged . Enzyme determinations were performed by Prof . Hers in a piece of the liver ; he showed that debranching enzyme was deficient . The urobilinuria, the high values for SGPT and SGOT (Table t) and the results of the biopsy indicated the presence of early cirrhosis- A series of glucagoninjections [28,29] had no effect on the size of the liver . in-7 . This patient, a girl, was admitted to the Paediatric Clinic at the age of nearly two years . She had a somewhat retarded mental development, but did not give the impression of being ill . From the age of about six months she suffered from repeated attacks of hypoglycemia . No abnormalities of the heart or lungs were noted . The liver was greatly enlarged ; the spleen could not be felt . Acetone and urobilin were absent from the urine . She was given frequent feedings rich in carbohydrate, which had been prescribed elsewhere, but 4 .5 hours after such a feeding she had convulsions . When the blood sugar content was determined a value of 29 mg . Per cent was found . The convulsions disappeared rapidly after the intravenous injection of glucose. When it became clear from the study of leukocyte enzymes that there was a deficiency of debranching enzyme, we gave the patient a protein-rich diet ; since then the convulsions have ceased . ut-8 and 9 . These patients are sisters, the eldest two of four children, both referred to us by Dr . Sorters (Breda) . There is no parental consanguinity . Both the patients were born at term . It was noticed that they started walking very late . They are often tired and show a great liking for bread . In the eldest, who is now more than six years old, the diagnosis of hepatomegalia was made at the age of about two years . In the younger, now five years old, hepatomegalia was recognized at the age of more than one year . Neither child had ever had any convulsions . On examination, both children had a very large liver ; the spleen was not palpable . In the urine the acetone test was weakly positive in the elder, and strongly positive in the younger child . In the younger child also, the urobilin test in the urine was positive . Enzyme determinations in the leukocytes and erythrocytes (Prof. Hers) of both children favored the diagnosis of glycogen liver disease caused by debranching enzyme deficiency . vi . We saw four patients with liver phosphorylase deficiency .

AMERICAN JOURNAL OF MEDICINE

Glycogen Storage Disease

tan Creveld. Huijing

2 2B

Patient vi-4 . A, at the age of twenty months_ 13, at the age of fourteen years. FIG . 2 .

vi-l . The case history of this patient, a boy, has already been described in detail elsewhere [30] . vi-2 . Another boy was admitted to the Paediatric Clinic at the age of three years because of a large liver and frequent fractures . He was the second of four children of healthy parents . At the age of two years he had his first fracture, at the age of three a second, it was then that the enlarged liver was noted . Biopsy was performed elsewhere, resulting in the diagnosis of glycogen liver disease . The patient never had convulsions . Except for a very large liver, we found no abnormalities in this boy, who mentally was normal . In the urine, the acetone test was sometimes positive, the urobilin test was always negative . Enzyme studies of the leukocytes pointed to a phosphorylase deficiency . At the age of five years this patient had another fracture . vi-3 . This male patient came to our clinic for examination at the age of thirteen years . He is the second of three children ; the parents are second cousins . The patient has been cyanotic since birth . When he was four months old it was fairly certain that he had an enlarged liver . He had several slight attacks of hypoglycemia . The enlargement of the liver was thought to be caused by the accumulation of glycogen and the patient was treated with a proVOL .

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tein-rich diet, following which the convulsions disappeared . We saw a very thin boy with peripheral cyanosis and a large liver . In the urine the acetone test was positive, diacetic acid weakly positive . Leukocyte phosphorylase activity was low . vi-4 . i'his boy was examined for the first time at the age of nearly two years . 'f he maternal grandmother of the patient was a sister of the paternal grandfather . At present he has eight brothers and sisters but he is the only one with glycogen liver disease . At the first examination we found a very large liver (Fig. 2A) but no enlargement of the spleen . Laboratory investigations confirmed the diagnosis of glycogen liver disease . We were able to examine him again at the age of fourteen years . The liver was palpable only 2 fingers below the costal margin . (Fig . 2B) He is in excellent condition and has no complaints . From the data in Table i it is clear that he is deficient in phosphorylase . COMMENTS

In consideration of the data reported in Table t we have come to the conclusion that since there was one specific enzyme deficiency . only one type of glycogen disease existed in all of our patients . In none of them did we notice a

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Glycogen Storage Disease-van

simultaneous deficiency of more than one enzyme, as has been found by some investigators [31-341 . In some of our cases it was not possible to perform all the necessary enzyme determinations, either because the patient was too ill or because the test method was not yet available . However, even in these cases there was no indication of the existence of a double enzyme deficiency . In both of our patients with glucose 6-phosphatase deficiency an increased lactate content of the blood was always found in the fasting state . The glycogen content of the blood was more or less increased in all the patients with debranching enzyme deficiency . With the exception of the three adult patients, SCOT and SGPT values were high in all patients with debranching enzyme deficiency . (Table t .) In the patient with the highest values (m-5), they decreased rapidly and markedly after the administration of small amounts of prednisone . The patients with normal SCOT and SGPT values were in excellent condition . The SCOT and SGPT activities were increased in only one of the three patients with phosphorylase deficiency . In one of the patients with glucose 6-phosphatase deficiency the high lactic acid content of the blood was accompanied by normal SGOT values, but with very high levels of plasma lactate dehydrogenase . The future will reveal whether SCOT and SGPT determinations are of prognostic value . With regard to the clinical features, it should be noted that repeated fractures occurred during the youth of our eldest patient, who is now forty-two years old and has a debranching enzyme deficiency, and in a boy with liver phosphorylase deficiency . One patient with debranching enzyme deficiency and a boy with phosphorylase deficiency showed a hemorrhagic tendency in youth . We determined the sodium content of the sweat in three patients, each with a different hepatomcgalic type of glycogen disease . In none of these cases was the sodium content increased, being 16 .3 mEq . per L . in a case of glucose 6-phosphatase deficiency, 44 .4 mEq . per L . in a case of debranching enzyme deficiency, and 65 .2 mEq . per L, in a case of phosphorylase deficiency . This is in contrast to the findings of Harris and Cohen [261 . These investigators found an increase in patients with glucose 6-phosphatase deficiency . As dietary therapy we gave patients with

Creveld, Huijing

ketosis a nonketogenic diet, poor in fat and rich in carbohydrates ; patients with glucose 6-phosphatase deficiency a diet without fructose and low in galactose, therefore no saccharose, no fructose-containing fruits and little or only lactose-poor milk ; and patients with debranching enzyme deficiency who had convulsions, an evening meal rich in proteins . SUMMARY

The clinical and biochemical data in sixteen patients with various types of glycogen storage disease are summarized . It is possible to make the differential diagnosis of this disease from the investigation of leukocyte enzymes and the in vivo transformation of galactose . Several suggestions for dietary therapy are made . ADDENDUM

Since this article was submitted, two further cases of glycogen storage disease with hepatomegalia have been observed . One, a case of debranching enzyme deficiency in a one and a half year old girl, came to our clinical attention during a severe attack of hypoglycemia . By giving her a protein-rich meal at night, the attacks of hypoglycemia subsided and have not recurred to date (observation period, ten months) . The other, a case of phosphorylase deficiency in the leukocytes, was in a one and a half year old boy who was a cousin of patient S . S . (Table i, vi-4 .) REFERENCES

1 . HERS,

and DE DUvE, C . Repartition de l'activite glucose .6-phosphatasique dans les tissues. Bull. Soc . chim . biol., 32 : 20, 1950 . 2 . LEJEUME, N ., TI-IINES-SEMPOUx, D . and HERS, H . G. Intracellular distribution and properties of alphaglucosidases in rat liver . Biochers . J., 86 : 16, 1963 . 3 . HERS, H. G . Alpha-glucosidase-deficiency in generalized glycogen-storage disease (Pompe's disease) . Biochem . J., 86 : 11, 1963 . 4 . KRtvrr, W., POLGLASE, W. J ., GUNN, F . D. and TYLER, F . H. Glycogen storage disease primarily affecting skeletal muscle and clinically resembling amyotonia congenita . Pediatrics, 12 : 165, 1953 . 5 . VAN CREVELD, S. Blackader Lecture 1962 : the clinical course of glycogen disease . Caned. M. A . J., 88' 1, 1963. 6 . CORI, G . T . Glycogen structure and enzyme deficiencies in glycogen storage disease. Harvey Lect ., 48 : 145, 1954. 7 . STEINITZ, K ., BODUR, H. and ARMAN, T . Amylo-1,6glucosidase activity in leucocytes from patients with glycogen storage disease . Clin . chin . acta, 8 : 807, 1963 . 8. HERS, H . G . Personal communication . 9 . WITTIAMS, H . E ., KENmc, E . M . and FIELD, J . B . H . G.

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Glycogen Storage Disease-van Crereld, Huging Leucoeyte debrauching enzyme in glycogen storage disease . J . Cin . Invest ., 42 : 656, 1963, 10 . (a) HcquNG, P . Amylo-1,6-glucosidasc activity in normal leucocytes and in leucocytes of patients with glycogen storage disease . Clin . chim . aria, 9 : 269, 1964 . (b) Hcg7NC, F . linzymafwijkingen in het perifere bloed hij glyeogeenziekte . Thesis. Amsterdam, 1964 . 11 . HERS, 11 . G. Recent developments in the biochemistry of glycogen storage disease and of fructose intolerance . Chemisch Weekblad, 57 : 437, 1961 . 12 . SmsuRv . J . B ., CORNBLArn, M ., FISHER, J . and HOUSE, E . Glycogen in erythrocytes of patients with glycogen storage disease . Pediatrics, 27 : 103, 1961 . 13 . HERS, H . G . Etudes enzymatiques sun fragments hepatiques. Rev . Int . Hfpetol_, 9 : 35, 1959 . 14 . (a) HULSMANN, W . C ., OEI, T . L . and VAN CREVELD, S . Phosphorylase activity in leucocytes from patients with glycogen-storage disease . Lancet, 2 : 58, 1961 . (6) OFT, T . L . Over glyeugecnziekte en favisme . Thesis . Amsterdam, 1964, 15 . WILLIAMs, H . E . and FIRLD, J- B . Low leucocyte pllosphorylase in hepatic phosphorylase-deficient glycogen-storage disease . J. Clin . Invest ., 40 : 1841, 1961 . 16 . l IcxGE rI, A . ST . G . and NIXON, D . A . Enzymic determination of blood glucose . Biochem . J ., 66 : 12, 1957 . 17 . HOHORST, H . J . Enzymatische Bestimmung von L(+)-Milchsaure . Biochem . Ztschr-, 328 : 509, 1957 . 18 . CONNLR'rV, H . V ., BRIGGS, A. R . and EATON, E . H . Simplified determination of the lipid components of blood serum . Clin . Chem ., 7 : 37, 1961 . 19 . ne VRIES . L . A . and VAX DAATSELAAR, J . J . Zie Klinisehc Diagnostiek, 7e druk, deel I, p. 281 . Edited by Getter, E . and de Graatf, W . C . Leiden, 1955 . Stenfort Kroese . N. V. 20 . HAssln, W . % . and ABRAHAM, S . Chemical procedures for analysis of polysaccharides. In : Methods in Enzymology, 3rd ed ., p . 34 . Edited by Colowick, S . and Kaplan, N . 0 . New York, 1957 . Academic Press .

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21 . SCHWARTZ, R ., ASHMORE, J . and RLV,un . A . F„ Galactose tolerance in glycogen storagr disease Pediatrics, 19 :585, 19.57 . 22 . BROMBACHER, P . J ., VAN CREVELD, S ., DAMM} ., ,h P ., Hugtdc, F . and PLOEM, J . E . A report on two adult patients with glycogen storage disease . Acta med . scandtnar., 176 : 269, 1964 . 23 . HcgING, F., VAN CREVELD, S . and LosuKllorr, G . Diagnosis of generalized glycogen-storage disease (Pompe's disease) . J, Pediat„ 63 : 984, 1963 . 24 . VAN CREVELO, S . and HmpNG, F. Differential diagnosis of the. type, of glycogen disease in two adult patients with long history of glyengenosis . .bletaholism, 13 : 191, 1964 . 23 . BRIDGE, E . M . and Host, 1 . . E . Glycogen storage disease. Observations on the pathologic physiology of two cases of the hepatic form of the disease . J. Pediat., 27 : 299, 1945 . 26 . HARRIS, R. C . and COHEN, H . J . Sweat electrolytes in glycogen storage disease, type L Pediatrics, 31 : 1044, 1963 . 2' . SHWACHMMAN, H. Sweat electrolytes in glycogen storage disease, type I . Pediatrics, 32 : 48, 1963, 28 . GITZELMAN, R . Glukagon Probleme bci den Glykogenspeieherkrankheiten . Ilelvet . paediat . Acta . 12 : 425 . 1957 . 29 . SOKAL, J . E . . I .OwE, C . Lf ., SARCIONE, I' . . J ., MOSOVIcE, L . I . and DOZAY, B . H . Studies of glycogen metabolism in liver glycogen disease : six cases with similar metabolic abnormalities and responses to glueagon . J . Clin . Invest., 40 : 364 . 1961 . 30 . VAN CREVELD, S . A new type of glycogen disease . J. Maine M. A ., 53 : 94, 1962 . 31 . ILLINGWORTH, B . Glycogen storage disease . Am . J . Cin. Nutrition, 9 : 683, 1961 . 32 . WAGNER, R. and SPARACO, R . Deficiency of phosphorylasc in glycogenosis, associated with deposit of abnormal glycogen in the liver . Arc . J. Dis . Child., 100 : 789, 1960 . 33, Lowe, C . U ., SOKAL, J . E ., MosovicH, L . L ., S .ARCIONE, E . J_ and DOZAY, B. 11 . Studies in liver glycogen-disease. Am . J . Med ., 33 : 4, 1962 . 34, Pesu orr G . T, PARKER, V . J_ and HAHN, R. F . The effects of glucagon in three forms of glycogen storage disease . J. Clin . Invest ., 4 : 1099, 1962 .