A mild juvenile variant of type IV glycogenosis

A Mild Juvenile Variant of Type IV Glycogenosis Erich Reusche, MD, Fuat Aksu, MD, Hans H Goebel, MD, Yoon S Shin, PhD, Tadaaki Yokota, MD and Heinz Reichmann, MD

The mild juvenile form of type IV glycogenosis, confirmed by a profound deficiency of the brancher enzyme in tissue specimens is reported from three Turkish male siblings who, foremost, suffered from chronic progressive myopathy. Muscle fibers contained polyglucosan inclusions of typical fine structure, i.e. a mixture of granular and filam~tous glycogen. They reacted strongly for myophosphorylase, but were resistant to diastase. These inclusions were ubiquitinated and reacted with antibody KM-279 which previously has been shown to bind to Lafora bodies, corpora amylacea and polyglucosan material in hepatic and cardiac cells of type IV glycogenosis as well as polyglucosan body myopathy without brancher enzyme deficiency. Our findings confirm that although rare, a mild form of type IV glycogenosis is marked by polyglucosan inclusions not only in myofibers, but also in smooth muscle and sweat gland epithelial cells. This fUrther implies that when polyglucosan inclusions are observed within myofibers it is mandatory to examine the muscle tissue for brancher enzyme activity since the brancher enzyme activities in circulating erythrocytes and leucocytes were normal in all three affected siblings and their parents. Therefore, it can be concluded that the patients reported on here represent a variant form of type IV glycogenosis, in which the defect is limited to muscle tissues. This further indicates that there are several different types of type IV glycogenosis with variable clinical manifestations. Key words: Brancher enzyme, electron microscopy, immunohistochemistry, juvenile form, polyglucosan inclusions, type IV glycogenosis. Reusche E, Aksu F, Goebel HH, Shin YS, Yokota T, Reichmann H. A mild juvenile variant of type IV glycogenosis. Brain Dev 1992; 14:36-43

Polyglucosan inclusions (PI) or polyglucosan bodies (PB) are a telltale hallmark of numerous cell types in numerous disorders when tissue sections are stained with the periodic acid Schiff (PAS) reagent. They have been encountered within axons of aging rats [1], in smooth muscle cells of aging dogs [2], within axons in diabetic poly-

From the Departments of Pathology (ER) and Neuropediatrics (FA), Medichl University of Lubeck; Division of Neuropathology, University of Mainz (HHG); Department of Pediatrics, University of Munich (YSS); First Department of Pathology, Yamaguchi University crY); Department of Neurology, University of Wtirzburg (HR). Received for pUblication: June 11, 1991. Accepted for pUblication: November 6, 1991. Correspondence address: Dr. E. Reusche, Department ofPathology, Medical University of LUbeck, Ratzeburger Allee 160, 2400 Lubeck 1, Germany. Parts of this paper were presented at the Annual Meeting of the German Neuropediatric Society, Gottingen 1989 and at the 5th International Child Neurology Congress, Tokyo, 1990.

neuropathy [3], in experimental murine diabetes [4] and in alloxan induced diabetes mellitus of rats [5]. In man, they may be encountered as corpora amylacea, i.e. within astrocytic processes, having been described in the lateral pallidum [6,7], within neurons in amyotrophic lateral sclerosis [8] or as a consistent morphological phenomenon within neurons in Lafora disease, then called Lafora bodies. In this latter disorder, similar PI have been recorded in hepatic and eccrine sweat gland cells. Certain disorders display multiorgan involvement by PI formation, among them hereditary type N glycogenosis based on a defect of the brancher enzyme. In other conditions, striated muscle fibers are predominantly affected. Basophilic degeneration of the heart, hypothyroidism [9] and polyglucosan body myopathy [10, 11] without brancher enzyme deficiency are among such conditions. Infantile type N glycogenosis, also called amylopectinosis or Andersen disease [12, 13], shows ubiquitous formation of PI in cerebral, hepatic and muscle cells. In this form of type N glycogenosis, based on a defect of the brancher enzyme [14,15], patients die at an average age of four

years of liver cirrhosis or cardiomyopathy [16, 17]. While the infantile form of type IV glycogenosis represents, within the spectrum of glycogenosis, the classical one, a milder, juvenile variant has only rarely been recorded [18-21]. It is the purpose of this paper to report on the mild or juvenile variant of type IV glycogenosis, predicated upon a profound deficiency of the brancher enzyme, in three male siblings marked by a predominant, but not exclusive, formation of PI in skeletal myofibers. Clinical symptomatology of a myopathy distinguishes this mild variant of type IV glycogenosis from the severe infantile form while the deficiency of the brancher enzyme, juvenile onset of clinical symptoms, and presence of PI outside of the skeletal muscle distinguish mild type IV glycogenosis from polyglucosan body myopathy with normal brancher enzyme activity in skeletal muscle.

kinase, aldolase, lactate dehydrogenase, GOT and GPT. The ischemic lactate test revealed a normal rise of lactate and normal values for creatine kinase and aldolase. The results of biochemical studies are given in Table 2. Conduction velocities of his peroneal and sural nerves were within normal limits, electromyography revealed increased polyphasic potentials. This boy is the fourth of six children from a consanguineous marriage. Both parents (first degree cousins), father 40 years old, mother 41 years old, are healthy. A 22-year-old sister and a 20-year-old brother are also healthy. One brother drowned at the age of 2 1/2 years, another older brother is patient 2 and another 1 1/2year-old brother is patient 3.

Table 1b Ancillary data of three boys with juvenile type IV glycogenosis Patient 1

Patient 2

9 2.70 227 15 14

31 ND 201 1.5 7

15

9

ND

ND

ND

98

94

ND

3.50

ND

ND

None

None

ND

Lipid-electrophoresis

N

ND

ND

Amino acids

N

ND

ND

Autoantibodies against striated muscle fibers

None

None

ND

Myoglobinuria

None

None

ND

Negative

ND

ND

CLINICAL DATA (Tables 1a and 1b) Patient 1 This 6-year-old Turkish boy developed, after normal pregnancy and delivery, muscle weakness, especially when climbing stairs or riding his bicycle. Clinically, he showed mild muscle hypotrophy and weakness, especially of his legs, Gowers sign, and absent knee and ankle jerks. There were no sensory deficits, cerebellar, or pyramidal signs. He was mentally normal. His liver appeared 1 cm below the right costal margin, his spleen 3 cm below the left costal margin. He had normal blood values of creatine

Table la

Clinical data of three boys with juvenile type IV glycogenosis

History Motor development Easy fatiguability Freq uent falls Abnormal gait Mental development Clinical fmdings Muscle hypotonia Muscle weakness Hyporeflexia Lumbar lordosis Winged scapulae Gowers' sign Hepatomegaly Splenomegaly Cardiac findings

Patient 1 AD

Patient 2 FD

Patient 3 AD

Delayed + + + Normal

Delayed + + + Normal

Delayed + + (+) Normal

+ + (+)

+ + (+)

+

+ +

+ +

1cm 3 cm Normal

+ 2cm 3cm Normal

+ (+)

Laboratory data CK (n: up to 50 U/1) Aldolase (n: up to 4.5 U/1) LDH (n: 120-270 U/!) GOT (n: 2-27 U/1) GPT (n: 5-24 U/1) Gamma-GT (n: 8.8 + 4.2 U/l) Blood gases pH (n: 7.35-7.45) p CO2 (n: 35-45 mm Hg) bicarbonate (n: 20-26 mmol/1) Blood glucose (n: 50-100 mg/dl) Lactate (+ ischemic test) (n: 3.72-1.53 mmol/1) Intracellular storage process in circulating blood cells

Myasthenia diagnostic (EMG + edrophonium test) EMG

+

Normal

ND ND

ND ND ND

7.44 35.9 24.9

(max)

Increased Increased rate of rate of polyphasic polyphasic po ten tials po ten tials

NCV (N. peronaeus, N. suralis)

Patient 3

N

N

ND

ND

N: normal, ND: not done, EMG: electromyogram, NCV: nerve conduction velocity.

Reusche et al: Type IV glycogenosis 37

Biopsies were perfonned on the left gastrocnemius muscle and the sural nerve, while a liver biopsy was refused. At the time of surgery for ileocecal invagination when he was three years old, his appendix had been removed.

and electrophysiological data were identical to those of patient 1. Biochemical data are given in Table 2. Biopsies were perfonned on the left M. gastrocnemius, N. suralis, and skin while a liver biopsy was refused. Appendicitis necessitated appendectomy two months later.

Patient 2 This 8-year-old boy, the older brother of patient 1, also had motor retardation and displayed easy fatiguability and an abnonnal gait. He did not show mental impairment. His liver was 2 cm below the right costal margin, his spleen 3 cm below the left costal margin. Laboratory

Patient 3 This 1 1/2-year-old boy, the youngest brother of patients 1 and 2, also fatigued rapidly, fell frequently, was hypotonic while muscle weakness was mild, and showed Gowers' sign. In view of the established disease in his family and extensive examination of the older affected

Table 2 Biochemical data in the family with juvenile type IV glycogenosis Enzyme (units/g/muscle)

Branching enzyme (nmol/min/mg/protein) Phosphorylase-b-kinase (~mol/min/mg/protein) Glycogen (g%) Phosphorylase Phosphofructokinase Phosphoglycerate kinase Phosphoglycerate mutase Lactate dehydrogenase

Glycogen (mg%) in erythrocytes Branching enzyme (nmol/min/mg/protein) in erythrocytes in leukocytes

Patient 1

Patient 2

0 2.7 2.1 20 37.4 119 228 240

0.064 10.3 3.1 ND ND

NO NO NO

NO

Patient 1

Patient 2

Patient 3

4.6 7.2 0.27

4.0 7.0

Controls' range (n = 50)

Patient 3

ND

0.3-3.0 2.0-15.0 up to 2.0 12.6 ± 3.95 25.9 ± 12.2 253 ± 105 290 ± 104 300 ± 165

NO ND ND

NO ND ND

3.5 9.0 0.27

Parents (m/fJ

Controls (n = 30)

3.7/4.2 6.7/6.8 10.19

0-10 5.0-15.0 0.15-0.50

Fig 1 Numerous polyglucosan inclusions (light areas) within muscle fibers which show considerable variation in fiber diameters. Modified trichrome stain. x 400.

Fig 2 Polyglucosan inclusions are strongly PAS-positive (dark). PAS stain. x 580.

38 Brain & Development, Vol 14, No 1, 1992

brothers, no further investigations were conducted and no biopsies were performed.

MATERIALS AND METHODS Biochemical determination of the brancher enzyme activities in skeletal muscle and blood cells was performed, according to published techniques [22,23]. Skeletal muscle specimens were rapidly frozen in isopentane, cooled in liquid nitrogen for biochemical study,

and also submitted to a battery of routine histological, immunological and enzyme histochemical methods. Separate specimens of the muscle, the appendices, the skin, and the sural nerve were fIxed in buffered glutaraldehyde and embedded in plastic. One p.rn thick plastic sections served for histological examination and for selection of ultrathin sections for electron microscopy.

Fig 3 The polyglucosan inclusions are resistant to diastase and still stain strongly with PAS (dark). x 500. Fig 4 The polyglucosan inclusions show strong activity ofmyophosphorylase (dark). x 400.

Fig 5 Polyglucosan inclusions do not give enzyme activity (light areas) and are largely found in type II fibers which are frequently atrophic. Alkaline ATPase. x 460. Fig 6 Polyglucosan inclusions react with the antibody KM·279. x 700.

Reusche et al: Type IV glycogenosis 39

MORPHOWGICAL DATA As findings in biopsied tissues of patients 1 and 2 were identical they will be described together. The gastrocnemius muscles contained polygonal muscle fibers ranging between 15 and 4O.um with a few internally located nuclei. Numerous polyglucosan inclusions (PI) were located largely in sub sarcolemmal regions (Fig 1), but also deeper inside myofibers which were strongly PAS-positive (Fig 2) and resistant against digestion with diastase (Fig 3). Phosphofructokinase and myophosphorylase preparations

gave regular histochemical reactions of myofibers, while the PI reacted strongly in the total myophosphorylase, myophosphorylase a, and myophosphorylase b preparations (Fig 4). Lugol's iodine solution alone did not stain the PI. They did not react in the NADH tetrazolium reductase, menadione linked alpha-glycerophosphate dehydrogenase and cytochrome-c-oxidase preparations. They were not rich in histochemical acid phosphatase or non-specific esterase activities . .There were checkerboard patterns of type I and type II fibers based on ATPase pre-

Fig 7 Polyglucosan inclusions are ubiquitinated (dark areas}. x 875. Fig 8 The polyglucosan inclusions within muscle fibers are largely filamentous with some granular glycogen. x 26,400.

Fig 9 The filamentous material is strongly stained with thiosemicarbazide, according to Thiery. x 26,400. Fig 10 Appendix: There are numerous PAS-positive polyglucosan inclusions. x 1,330.

40 Brain & Development, Vol 14, No 1,1992

parations with type I fiber predominance. The PI were largely found in type II fibers which were then frequently atrophic (Fig 5). PI reacted strongly with the antibody KM 279 [24, 25] (Fig 6) and with an antibody against ubiquitin (Fig 7), but not with antibodies against desmin, vimentin, and dystrophin. By electron microscopy, myofibers contained PI that consisted of granular glycogen and fllaments (Fig 8) which were also identified as glycogen when ultrathin sections were stained with thiosemicarbazide (Fig 9) [26]. PAS-positive PI were also present in smooth muscle cells of the appendix in patient 2 (Fig 10), but not in those of patient 1 at the age of three years and, by electron microscopy, in epithelial cells of eccrine sweat glands of patient 2 (Fig 11 a, b). The sural nerve lacked polyglucosan inclusions or any other significant abnormalities.

DISCUSSION The familial condition in our three male siblings was clinically marked by neuromuscular symptoms, showing spectacular polyglucosan inclusions within muscle fibers suggesting polyglucosan body myopathy, a neuromuscular disorder which is known to occur without a brancher enzyme defect [10, 11,27,28]. Conversely, our patients' muscle tissues were deficient in brancher enzyme activity identifying their neuromuscular disorder as type IV glycogenosis. Activity of phosphofructokinase in our patieRts' muscle tissues eliminated type VII glycogenosis as the nosological equivalent of this polyglucosan storage which has earlier been shown to occur in phosphofructokinase deficiency [29, 30]. The presence of similar poly-

glucosan bodies in smooth muscle cells of the appendix and sweat gland epithelia attested to the generalized pattern of this polyglucosan storage. Clinical symptomatology and clinical course distinguish our patients' type IV glycogenosis from the more frequent infantile form which itself is rare among other nosological types of glycogenoses [16]. The mild or non-infantile form of type IV glycogenosis has been identified in only a few instances (Table 3) [18-21,31,32]' but the clinical spectrum concerning the chiefly affected organ is variable because, apart from a myopathy observed in our-and another [31] -patients, cardiomyopathy [20] or hepatopathy [18, 19, 21] may prevail. A biopsy is essential for diagnosis. The normal activity of the brancher enzyme in our patients' circulating blood cells is, so far, unexplained, but underscores the organ-limitation of this variant of type IV glycogenosis, possibly based on different isoforms of the brancher enzyme and their different involvement in different forms of type IV glycogenosis. While several routine enzyme-histochemical preparations revealed the polyglucosan inclusions (PI) devoid of respective enzyme activities two aspects deserve particular notion. The PI were largely located in type II myofibers which themselves had undergone atrophy, whilst in polyglucosan body myopathy without brancher enzyme defiCiency PI were chiefly encountered in type I fibers [10,28,33,34], but only rarely in type II fibers [11,35]. This unexplained observation may, perhaps, serve as a differential diagnostic aspect distinguishing the two forms of PI-related myopathies. The other aspect worth mentioning is the strong reaction of the PI in total myophosphorylase preparations which had also repeatedly been

Fig 11 Sweat glands: a) Numerous sweat gland epithelial cells show circumscribed PI One JJ.m thick epon·embedded section, toluidine blue. x 1,400. b) By electron microscopy, the PI show the typical filamentous pattern. x 24,000.

Reusche et al: Type IV glycogenosis 41

Table 3 Mild form of type IV glycogenosis Patient/gender [reference}

Reduced activity of branching enzyme (amylo-1 ,4-1,6 transglucosidase/ alpha-1,4 glucan: alpha 1,4 glucan 6 -glucosyltransferase)

Familial

Most prominent clinical sign

26-59 y / male [31)

No

Muscle weakness

Muscle: 50% leucocytes: low normal

8 y / female [19)

No

Hepatosplenomegaly

Cultured fibroblasts

18-19 y / male [18)

3 male siblings

Liver cirrhosis

Data not given

8 1/2 y / female [20)

No

Cardiomyopathy

No activity in muscle (biopsy), liver, heart (autopsy); 10% brain (autopsy)

5y/male [21)

No

Hepatomegaly

Liver (10%), muscle (0), cultured fibroblasts (0)

3 male sib lings

Muscle weakness

Muscle: 0-2% of normal, leucocytes and erythrocytes normal

2 1/2-9 y /male [32) and this paper

seen in PI of polyglucosan body myopathy without brancher enzyme activity [10, 28, 33, 35] while Lugol's iodine solution did not stain the PI in polyglucosan body myopathy and mild type IV glycogenosis. This strong histochemical reaction for myophosphorylase of PI which is supported by an above normal biochemical activity of phosphorylase in one of our patient's skeletal muscle (Table 2) seems to indicate an adaptive phenomenon induced by the formation of the PI. However, a similar increased activity of phosphofructokinase was not encountered histochemically and biochemically in one of our patient's muscle specimen. These observations common to PI in mild type IV glycogenosis and polyglucosan body myopathy attest to the chemical similarity of the stored polyglucosan in addition to the light and electron microscopic features including the more conspicuous demonstration of the f:tlaments by the Thiery technique, and are further corroborated by immunological reactions with antiubiquitin and the KM-279 antibodies [24, 25, 28]. The KM-279 antibody also reacts with Lafora bodies, corpora amylacea, polyglucosan inclusions of liver and heart in type IV glycogenosis and the material encountered in basophilic degeneration of the heart [24,25]. The PI appear ubiquitinated, i.e. rendered for lysis as ubiquitin has been found in numerous types of other inclusions such as Pick and Lewy bodies, neurofibrillary tangles, Rosenthal fibers, hepatic Mallory bodies and skeletal muscle cytoplasmic bodies [36,37], the latter two also containing respective intermediate f:tlaments keratin and desmin [38, 39]. However, the PI were negative for desmin. A further distinction between mild type IV glycogenosis and polyglucosan body myopathy without brancher enzyme deficiency is the repeatedly observed presence of

42 Brain & Development, Vol 14, No 1,1992

abnormally structured mitochondria in the latter [10,28, 34,35,40,41]. This may reflect mild differences of the PI in affecting their immediate environment or chiefly the chronicity of the lesions because polyglucosan body myopathy with abnormal mitochondria around PI in myofibers is largely a disorder of adults. Normal activities of the brancher enzyme in circulating erythrocytes and leucocytes suggested that the juvenile type IV glycogenosis of our patients has not affected every type of cell and organ. Thus, we may deal with a variant of juvenile type IV glycogenosis within the entire spectrum of the brancher enzyme deficiencies. Our fmdings suggest further that testing only circulating blood cells for brancher enzyme activity may be inadequate to detect each form of type IV glycogenosis, whereas a biochemical test for brancher enzyme activity appears mandatory, whenever PI are encountered within muscle fibers. ACKNOWLEDGMENTS We are grateful for the antibody against ubiquitin provided by Prof. Schiffer, Chairman, Dept. of Neurology, Univeristy of Torino, Italy. We are also grateful to Mrs. M. Schlie, Mrs. I. Wario, Mr. W. Meffert, and Mrs. M. Messerschmidt for their respective enzyme- and immunohistochemical, electron microscopic, photographic, and secretarial assistance. REFERENCES 1. Thomas PK, King RHM, Sharma AK. Changes with age in the

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Reusche et al: Type IV glycogenosis 43