Lipid storage myopathy in von Gierke's disease

Journal of the Neurological Sciences, 1978, 38:195-205

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© Elsevier/North-Holland Biomedical Press

LIPID STORAGE MYOPATHY IN VON GIERKE'S DISEASE A Case Report

KOHEI YAMAGUCHI*, TETSUSHI SANTA, KENJIRO INOUE and TERUO OMAE Second Department of Internal Medicine and Department of Neurology, Faculty of Medicine, Kyushu University, Fukuoka, 812 (Japan)

(Received 6 March, 1978) (Accepted 2 May, 1978)

SUMMARY An 18-year-old girl with von Gierke's disease associated with a lipid storage myopathy is reported. The diagnosis of von Gierke's disease was made from decreased activity in glucose-6-phosphatase in the jejunal biopsy specimen. Neurologically she showed generalized hypotonia of the muscles, atrophy of bilateral proximal muscles of the lower extremities, weakness in neck flexors, deltoid and lumbar girdle muscles, and a positive Gowers' sign. Muscle biopsy from flexor femoris muscle revealed fatty deposition in type 1 fibers and atrophy of type 2 fibers and the diagnosis of an accompanying lipid storage myopathy was made. This case also had a ventricular septal defect confirmed by right cardiac catheterization.

INTRODUCTION Since the first description of hepatorenal glycogen storage disease by Van Creveld in 1928 (cited from Van Creveld 1959), many cases of von Gierke's disease (glycogen storage disease type 1) have been reported. There has been, however, no report on a case of von Gierke's disease associated with myopathy. On the other hand, since the first report of a case of lipid storage myopathy (Bradley, Hudgson, Gardner-Medwin and Walton 1969), many case reports have been done on the disease. However, none of them were discussed in the relationship with glycogen storage disease (reviewed by Angelini 1976). Recently, we have encountered a case of yon Gierke's disease associated with * Present address: Department of Geriatrics, Institute of Constitutional Medicine, Kumamoto University, Kumamoto, 862 (Japan)

196 lipid s t o r a g e m y o p a t h y . In this p a p e r , we r e p o r t t h e o u t l i n e o f t h e case and discuss t h e differences a n d t h e similarities b e t w e e n o u r case a n d r e p o r t e d cases o f lipid s t o r a g e myopathy. REPORT OF A CASE This 18-year-old girl (N.T.) was born after a full term uneventful pregnancy and delivery. According to her mother, her physical development was slow compared with a corresponding child of normal development and she began to walk at the age of 3 years. At the age of 5 years, she had pneumonia. She has not suffered from a definite attack of hypoglycemia. Her school record was average. Menstruation has not yet begun. In the summer of 1973 (age 17) she experienced muscle weakness of both lower limbs during swimming. The complaint of weakness increased gradually and in the autumn, she could not go upstairs. In January, 1974 she could not stand without support and also became aware of myalgia in the thighs and forearms. In April, 1974 she was admitted to the Second Department of Internal Medicine, Kyushu University Hospital because of the myalgia and the delay in development. Family history. There is no consanguinity. The patient is the fifth of 6 siblings. The eldest brother has died as a result of "liver disease" at the age of 3 years and the younger brother showed similar symptoms as this patient with the exception of the neurologic abnormalities. Other siblings are well. Physical examination. A dwarf with trunk and extremities proportional, 132.2 cm in height and 29.4 kg in weight. She had a face of so-called "doll-like-appearance" (Fig. 1). On auscultation

Fig. 1. Patient N.T., aged 18 years, showing short stature, "doll-like appearance" and hepatomegaly.

197 of the heart sounds, a high-pitched systolic murmur with the maximal point at the left sternal border in the 4th intercostal space was audible. The abdomen was distended, 68.5 cm in circumference. There was venous dilatation in the abdominal wall. The liver was palpable 5-finger-breadths beneath the right costal margin, smooth and of moderately increased consistency. There was no pretibial edema and no lymphadenopathy. Neurologic examination. Consciousness was clear and orientation was good. Although the visual fields were normal, her central vision was moderately impaired. Ophthalmoscopic examination revealed star figure spots in the macula and edematous turbidity in the lower part of the retina of the right eye. The ocular movement was not disturbed and there was no nystagmus. No abnormality was observed in 5th to 12th cranial nerves. There was no nuchal rigidity or limitation of movement of the neck. There was generalized hypotonia and atrophy of the proximal muscles of the lower extremities. The power of neck flexor, deltoid and lumbar girdle muscles was decreased and Gowers' TABLE 1 LABORATORY EXAMINATION Normal values in brackets. Blood chemistry total bilirubin (mg/dl) alkaline phosphatase (mU/ml) LDH (mU/ml) GOT (mU/ml) GPT (mU/ml) total protein (g/dl) albumin (9/00) al-globulin ( ~ ) as-globulin (9/00) fl-globulin ( ~ ) ~'-globulin ( ~ ) cholesterol (mg/dl) triglyceride (mg/dl) lipid phosphate (mg/dl) fl-lipoprotein (mg/dl) Na (mEq/l) K (mEq/l) CI (mEq/1) Ca (mg/dl) P (mg/dl) uric acid (mg/dl) B U N (mg/dl) creatinine (mg/dl) serum iron Q~g/dl) creatinine phosphokinase (U/ml) lactic acid (mM/l) pyruvic acid (raM/l) lndocyanine green 15' retention rate ( ~ ) Renal function Fishberg (max.) PSP (15' %) (120'%) creatinine clearance (l/day) Arterial blood gas pH Po2 (mm Hg) Pco2 (mm Hg) HCO-s (mEq/l)

0.2 235 160 55 60 6.8 55.6 3.5 15.4 13.3 11.9 290 1137 21 1124 137 3.5 111 8.8 2.7 6.2 18 0.7 53 43.0 6.98 0.389 9.0 1012 3 16.5 37.3 7.305 97.5 20.8 9.9

(0.15-1.0) (30-85) (100-225)

(8-40) (8-40) (6-8) (55-65) (3-5)

(5-8) (9-13) (15-21)

(150-300) (30-135)

(5-1o) (150-500) (135-152) (3.5-4.5) (96-110) (8.5-10.5) (3-4.5)

(2.5-8.0) (10-20) (0.7-1.4) (100-170) (0-19) (0.58-1.26) (0.025~.093) ( < 10) ( > 1022) ( > 25) (60-85) (80-120) (7.35-7.45) (95-100) (35-40) (22-28)

198 sign was positive. Deep tendon reflexes were normal. There were no pathologic reflexes, sensory disturbances, adiadochokinesis, ataxia or involuntary movement. Laboratory examination. Urinary protein and glucose were negative but microscopic hematuria and excretion of urinary casts were noted. Hemogram was as follows; erythrocytes 188 × 10a/ram 3, hemoglobin 37 % (Sahli), hematocrit 21.5 ~ , leucocytes 6100/ram a with normal differential count and platelets 26.0 x 10a/ram a. There was no morphologic abnormality of erythrocytes or leucocytes. Erythrocyte sedimentation rate was 39 mm/hr and 93 ram/2 hr. The results of the tests for blood chemistry, hepatic and renal function, and arterial blood gas study are shown in Table I. Marked hyperlipemia, elevation of the levels of alkaline phosphatase and creatine phosphokinase were the most conspicuous findings. Renal function was moderately disturbed. The levels of lactic and pyruvic acid were also elevated. The arterial blood gas study suggested a metabolic acidosis. The following endocrine tests were within normal limits: urinary 17-hydroxycorticosteroid and ketosteroid, cortisol circadian rhythm, dexamethasone suppression test, rapid ACTH test and metopirone test. The serum thyroxine and Ta-resin uptake were 5.7 pg/dl and 21.7 %, respectively. Thyroid-stimulating hormone response to thyrotropin-releasing hormone was low. Follicle-stimulating hormone and luteinizing hormone (LH) response to LH-releasing hormone was exaggerated. The resting level of serum human growth hormone were fluctuated markedly (3.1-20.5 ng/ml) and it was not suppressed but was enhanced by 50 g oral glucose tolerance test and its response to glucagon stress was within normal limit (basal level; 3. I, peak; 14.8 ng/ml). A 50 g oral glucose tolerance curve and the response of immunoreactive insulin were normal. The findings of carbohydrate metabolism specific for yon Gierke's disease were as follows; decrease of the level of serum lactic acid in response to glucose loading and no normal elevation of blood glucose in response to glucagon or galactose injection (Fig. 2).

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Fig. 2. Glucose, glucagon and galactose tolerance tests. Blood sugar was measured with HagedornJensen's method except in the case of the galactose tolerance test. In the galactose tolerance test, the difference between the values with Hagedorn-Jensen and glucose-oxidas¢ at each point indicates the level of galactose.

Fig. 3. Histologic finding of the jejunal mucosa (H and E stain, × 400) showing presence of PASpositive substance under the nuclei of the villi.

Fig. 4. Frozen transverse section of left flexor femoris muscle. The muscle fibers show slight variation in size. There is fatty infiltration in the stroma. H and E stain, x 140.

200

Fig. 5. Frozen transverse section. This shows striking lipid excess, especially in red fibers (dark fibers). Sudan black B stain, .: 630. Skeletal X-ray examination revealed decalcification of long bones, opening of epiphyseal lines and spondylolisthesis (Ls). Bone age corresponded to a 12-year-old. Biopsy of jejunal mucosa was performed with the method of Crosby. Glucose -6-phosphatase activity in the biopsy specimen was 0.05 mg phosphate/g of wet tissue (normal 1.0-2.06) with themethod of Williams, Johnson, Fenster, Laster and Field (1963). Histologic examination (Fig. 3) showed the presence of periodic acid-Schiff (PAS) positive substances under the nuclei of the villi, which were digested by saliva. This substance, therefore, proved to be glycogen. An ECG showed ordinary sinus rhythm, left axis deviation, QT prolongation and blunt T. The results of intensive examination of the cardiac murmur by phonocardiographic study and right cardiac catheterization confirmed the presence of ventricular septal defect with small shunt volume. An electromyogram (EMG) of the right deltoid and triceps revealed low amplitude motor unit action potential and that of the vastus medialis revealed polyphasic units. Myotonic response was not seen. These findings suggested a myogenic pattern. Muscle biopsy. To elucidate the cause of the muscle weakness, muscle biopsy was done from the left flexor femoris muscle and each specimen was studied by a previously described technique (Santa 1969). The findings were as follows (Figs. 4, 5, 6 and 7). Light microscopy: Muscle fiber diameter ranged from 15-90/,m, with variation in size. Most of the muscle fibers consisted of two groups of fibers of diameter ranging from 50-60/~m and of approximately 20/~m. There was marked infiltration of fat but no increase in collagen fibers. Central

201

Fig. 6. This electron micrograph shows marked increase of vesicular structures, probably lipid in muscle fiber. There are no myofibrillar changes, x 11500.

nuclei or sarcolemmal nuclei were not increased in number. Large diameter fibers contained numerous small vacuoles with a diameter of 4 fire. There was little degenerative change in muscle fibers. Trichrome stain did not show any rod bodies or ragged red fibers. With PAS stain, there was no increase in PAS-positive substance. In reduced diphosphopyridine nucleotide (DPNH) staining, enzymatic activity of mitochondria was not elevated and the network of mitochondria was of normal pattern. Phosphorylase response was positive. Although fiber typing in myosin ATPase showed almost normal checker board, all the type 2 fibers were small in size. There was no elevation in acid phosphatase activity. In type 1 fibers, there was more marked infiltration of fat with Sudan black stain. Electron microscopy: There was fatty infiltration not only in muscle fibers but also in the endothelial cells of vessels. There was an increase of round-shaped fat droplets which were variable in size within the muscle cells and usually in close contact with mitochondria. Sequential course. From the above findings, the diagnosis of von Gierke's disease was made. Sodium bicarbonate (1.0 g/day and 4.0 g/day later) was administered to correct acidosis. Low fructose and lactose diet was given, in order to elevate blood lactate level resulting in enhancement of acidosis in this disease. Ten or twenty g of glucose in powder was given per day. Sutticient water intake was recommended strongly for preventing nephrolithiasis. In June, the serum level of uric acid had risen to 8.7 mg/dl, so 300 mg of allopurinol was administered per day. The above treatment resulted in moderate improvement of acidosis (from pH 7.305 to pH 7.348) and normalization of serum uric acid level (from 8.7 to 4.7 mg/dl). However, drug rash due

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Fig. 7. The lipid deposits are adjacent to or surrounded by mitochondria. "~::20,000.

to allopurinol obliged replacement of the drug with probenecid (1000 mg/day). The muscle weakness was relieved and Gowers' sign became negative in July, 1974. Little change had occurred in the serum lipid levels by July, 1974. DISCUSSION It is clear that this case is one of yon Gierke's disease because of the histological findings in the intestinal biopsy, the low titer in glucose-6-phosphatase activity in the biopsy specimen and the biochemical observations; decrease of the level of serum lactic acid in response to glucose loading (Fernandes, Huijing and K a m e r 1969) and the absence of normal elevation of blood glucose in response to glucagon (Fernandes et al. 1969) or galactose (Schwartz, Ashmore and Renald 1962). A number of biochemical abnormalities which might affect energy metabolism in muscle were detected; hypoglycemia, hyperlipidemia, hyperlactacidemia and lactic acidosis. They are, however, explained by the presence of yon Gierke's disease (Lowe, Sokal, Mosovich, Sarcione and Doray 1962; Howell 1968; Fernandes and Pikaar 1969). There has been no report which discussed the association of yon Gierke's disease

203 with congenital heart disease. But Friedberg (1966) said that cardiac anomalies have been associated with several chromosomal aberrations causing non-cardiac abnormalities as well, and with a variety of gene disorders. In our case, the muscle biopsy revealed fatty deposition within stroma and muscle fibers and there was definite muscle weakness. Lipid storage myopathy such as observed in our case has not yet been reported associated with von Gierke's disease. The muscle weakness in this case is also clearly different from that in muscle glycogenesis. Lipid storage myopathy was reviewed by Angelini (1976), recently. In his view, lipid storage myopathy can be classified into 4 categories, namely (l) carnitine deficiency, (2) carnitine-palmityl-transferase deficiency, (3) pyruvate-decarboxylase deficiency and (4) neutral-lipid storage disease. Carnitine deficiency was first reported by Engel and Angelini (1973). Thereafter, 7 cases were reported (Engel et al. 1973; Markesbery, McQuillen, Procopis, Harrison and Engel 1974; Karpati, Carpenter, Engel, Watters, Allen, Rothman, Klassen and Mamer 1975; Smyth, Lake, MacDermot and Wilson 1975; VanDyke, Griggs, Markesbery and DiMauro 1975; Angelini 1976; Angelini, Lficke and Cantarutti 1976). All the patients except one suffered from this disease during youth (the age of 18 months to 19 years). This disease is progressive and involves especially the proximal muscles. The patients respond to treatment with corticosteroids, a diet containing mediumchain fatty acid or the limitation of fat ingestion. The characteristic of the disease is the fat-containing vacuole of the leucocytes (Markesbery et al. 1974). These clinical manifestations do not accord with those of our patient who responded well to the treatment for von Gierke's disease and had no abnormality in leucocyte. There have been two reported cases with carnitine-palmityl-transferase deficiency confirmed by enzyme identification (DiMauro and DiMauro 1973; Bank, DiMauro, Bonilla, Capuzzi and Rowland 1975). The characteristics of this disease are said to be periodic "cramp" of muscles and myoglobinuria, which have no similarities to our case at all. One case with pyruvate decarboxylase deficiency has been reported (Blass, Kark and Engel 1971), which showed periodic ataxia and chorea-like movement but no definite muscle weakness. The levels of serum triglyceride and lactic acid were elevated in this case and the patient responded well to corticosteroids. The clinical manifestations do not resemble to those of our patient other than the elevation of triglyceride and lactic acid levels. One case which was reported as neutral-lipid storage disease (Chanarin, Patel, Slavin, Wills, Andrews and Stewart 1975) had vacuoles containing triglyceride in the systemic tissues and was associated with ichthyosis. The patient showed no abnormal value of serum lipids. These manifestations are not similar to those of our patient. About 4 cases have been reported other than the above as unclassified lipid storage myopathy (Bradley et al. 1969; Gullotta, Payk and Solbach 1974; Jerusalem, Angelini, Engel and Groover 1973; Jerusalem, Spiess and Baumgartner 1975). None of these cases have similar manifestations to our case. We should discuss the histologic findings on muscle biopsy in the cases with lipid storage myopathy mentioned above.

204 In carnitine-palmityl-transferase deficiency (DiMauro and DiMauro 1973; Bank et al. 1975), no marked deposition of lipid in muscles was reported. In carnitine deficiency (Angelini 1976: Engel et al. 1973) and pyruvate-decarboxylase deficiency (Blass et al. 1971), lipid excess occurred especially in type 1 fibers of muscles. In some cases with carnitine deficiency, the presence of many atrophic fibers and lipid droplets adjacent to mitochondria were revealed. Also in neutral-lipid storage disease (Chanarin et al. 1975), lipid excess was found especially in type I fibers in muscles. Bradley et al. (1969) reported the first case with lipid storage myopathy, in which the most impressive change was the presence of numbers of vacuolated fibers, some being subsarcolemmal and others being scattered throughout the fibers. This case is now known to have carnitine deficiency (Personal communication), In a case reported by Gullotta et al. (1974), the major findings on muscle biopsy were an increase of mitochondria and particularly of lipid droplets in the muscle fibers of type 1. In a case reported by Jerusalem et at. (1975) as lipid storage myopathy with normal carnitine levels, lipid excess was found both in type 1 and 2 fibers in muscles although more prominent in type I fibers. Electron microscopy demonstrated lipid excess and normal mitochondria by simple inspection. A case with mitochondria-lipid-glycogen disease of muscle was reported by Jerusalem et al. (1973), in which muscle biopsy revealed mild glycogen and marked lipid and mitochondria excess. In our case also, lipid excess was found in type 1 muscle fibers. Other histological findings were not specific. It can be said that the main histological features in our case are similar to the previously reported cases with lipid storage myopathy. Although enzymatic identification was not performed in our case, lipid excess in type 1 fibers and atrophy of type 2 fibers suggest the presence of abnormal energy metabolism in muscles resulting in lipid accumulation in muscle fibers and muscle weakness. Tendency to continuous hypoglycemia, hyperlactacidemia and hypertriglyceridemia in von Gierke's disease might have the stimulatory effect on the above mechanism. This possibility is increased when we consider that muscle triglyceride levels may increase depending upon the work imposed by exercise (Therriault, Beller, Smoake and Hartley 1973). As mentioned above, the lipid storage myopathy in our case cannot be classified into any type proposed by Angelini (1976). Our case is thought to be the first of von Gierke's disease associated with a lipid storage myopathy.

REFERENCES Angelini, C. (1976) Lipid storage myopathies - - A review of metabolic defect and of treatment, J. NeuroL, 214: 1-11. Angelini, C., S. L~ickeand F. Cantarutti (1976) Carnitine deficiency of skeletal muscle - - Report of a treated case, Neurology (Minneap.), 26: 633-637. Bank, W. J., S. DiMauro, E. Bonilla, D. M. Capuzzi and L. P. Rowland (1975) A disorder of muscle lipid metabolism and myoglobinuria - - Absence of carnitine palmityl transferase, New Engl. J. Med., 292: 443-449. Blass, J. P., R. A. P. Kark and W. K. Engel (1971) Clinical studies of a patient with pyruvate decarboxylase deficiency, Arch. Neurol. (Chic.), 25: 449-460. Bradley, W. G., P. Hudgson, D. Gardner-Medwin and J. N. Walton (1969) Myopathy associated with abnormal lipid metabolism in skeletal muscle, Lancet, 1 : 495-498.

205 Chanarin, I., A. Patel, G. Slavin, E. J. Wills, T. M. Andrews and G. Stewart (1975) Neutral-lipid storage disease - - A new disorder of lipid metabolism, Brit. med. J., 1 : 553-555. DiMauro, S. and P. M. M. DiMauro (1973) Muscle carnitine palmityl-transferase deficiency and myoglobinuria, Science, 182: 929-931. Engel, A. G. and C. Angelini (1973) Carnitine deficiency of human skeletal muscle with associated lipid storage myopathy - - A new syndrome, Science, 179: 899-902. Fernandes, J. and N. A. Pikaar (1969) Hyperlipemia in children with liver glycogen disease, Amer. J. Clin. Nutr., 22: 617-627. Fernandes, J., F. Huijing and J. H. Van de Kamer (1969) A screening method for liver glycogen diseases, Arch. Dis. Child., 44: 311-317. Friedberg, C. K. (1966) Diseases of the Heart, 3rd edition, Saunders, Philadelphia, PA, p. 1188. Gullotta, F., Th. R. Payk and A. Solbach (1974) Sudanophile (mitochondriale) Myopathie, Z. Neurol., 206: 309-326. Howell, R. R. (1968) Hyperuricemia in childhood, Fed.Proc., 27: 1078-1084. Jerusalem, F., H. Spiess and G. Baumgartner (1975) Lipid storage myopathy with normal carnitine levels, J. neurol. Sci., 24: 273-282. Jerusalem, F., C. Angelini, A. G. Engel and R. V. Groover (1973) Mitochondria-lipid-glycogen (MLG) disease of muscle - - A morphologically regressive congenital myopathy, Arch. Neurol. (Chic.), 29: 162-169. Karpati, G., S. Carpenter, A. G. Engel, G. Watters, J. Allen, S. Rothman, G. Klassen and O. A. Mamer (1975) The syndrome of st stemic carnitine deficiency - - Clinical, morphologic, biochemical, and pathophysiologic features, Neurology (Minneap.), 25: 16-24. Lowe, C. U., J. E. Sokal, L. L. Mosovich, E. J. Sarcione and B. H. Doray (1962) Studies in liver glycogen disease - - Effects of glucagon and other agents on metabolic pattern and clinical status, Amer. J. Med., 33: 4-19. Markesbery, W. R., M. P. McQuillen, P. G. Procopis, A. R. Harrison and A. G. Engel (1974) Muscle carnitine deficiency - - Association with lipid myopathy, vacuolar neuropathy, and vacuolated leukocytes, Arch. Neurol. (Chic.), 31 : 320-324. Santa, T. (1969) Fine structure of human skeletal muscle in myopathy, Arch. Neurol. (Chic.), 20: 479489. Schwartz, R., J. Ashmore and A. E. Renold (1962) Galactose tolerance in glycogen storage disease, Pediatrics, 19 : 585-595. Smyth, D. P. L., B. D. Lake, J. MacDermot and J. Wilson (1975) Inborn error of carnitine metabolism ("carnitine deficiency") in man, Lancet, 1 : 1198-1199. Therriault, D. G., G. A. Belier, J. A. Smoake and L. H. Hartley (1973) Intramuscular energy sources in dogs during physical work, J. Lipid Res., 14: 54-60. Van Creveld, S. (1959) Glycogen disease, Arch. Dis. Child., 34: 298-301. VanDyke, D. H., R. C. Griggs, W. Markesbery and S. DiMauro (1975) Hereditary carnitine deficiency of muscle, Neurology (Minneap.), 25: 154-159. Williams, H. E., P. L. Johnson, L. F. Fenster, L. Laster and J. B. Field (1963) Intestinal glucose-6phosphatase in control subjects and relatives of a patient with glycogen storage disease, Metabolism, 12: 235-241.