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Polyglucosan body myopathy: A new case
Neuromusc.Disord.,Vol.2. No. 5/6,pp. 419-.422.1992
0960-8966/92$5.00 + 0.00 01993 PergamonPress Ltd
Printed in Great Britain
CASE REPORT POLYGLUCOSAN
BODY MYOPATHY:
A NEW CASE
P. TONIN,* G. TOMELLERI, M. VIO a n d N. RIZZUTO Institute of Neurology, University of Verona, Verona, Italy
(Received 17 July 1992, revised 26 September 1992, accepted 2 October 1992) Abstract--We report a 51-yr-old woman with late-onset progressive weakness affecting
proximal limb muscles. Muscle biopsy revealed a vacuolar myopathy with accumulation of amylopectin-like polysaccharide resembling the polyglucosan found in type IV glyeogenosis and adult-onset polyglucosan body disease. A biochemical study ruled out specific enzymatic defects known to cause storage of this abnormal material. Our case confirms the existence of a 'polyglucosan body myopathy' as a distinct clinicopathological entity in which the biochemical defect is unknown. Key words: M y o p a t h y , polyglucosan, b r a n c h i n g enzyme.
on heels and was barely able to rise from a squatting position. There was weakness and wasting of proximal limb muscles; the patient was not able to lift her arms up to shoulder level and had a severely reduced abduction. Tendon reflexes were decreased. Sensation was normal. She had slight ptosis, but no dysphagia or dysphonia. There was no parental consanguinity and family history was negative for neuromuscular disorders. Routine blood tests were normal, including CK, aldolase and LDH. Thyroid function was normal. ECG showed incomplete right bundle branch block. The forearm ischemic exercise test was normal. E M G was myopathic and nerve conduction velocity was normal.
INTRODUCTION
Accumulation of a polysaccharide structurally similar to amylopectin has been reported in several disorders mainly affecting the central and peripheral nervous systems [1], but also heart [2], liver [3] and muscle [4]. The etiology in most of these diseases is unknown, but defects of brancher [3, 5] or phosphofruotokinase [6-8] enzymes have been described. Thirteen patients had progressive myopathy, with accumulations of amylopectin-like polysaccharide in muscle, but without known enzymatic defect [9]. We report a new patient with late-onset progressive myopathy and vacuolar deposits of filamentous polyglucosan.
RESULTS AND DISCUSSION CASE REPORT
A biopsy of the vastus la~ralis muscle showed vacuolar myopathy. The vacuoles, which had variable sizes, were located both in the center of the fibers and under the sarcolemma. They contained basophilic (Fig. 1) and strongly PAS-positive material (Fig. 2), which was only partially digested by alpha-amylase. Alcian blue and the stain for acid phosphatase activity were negative. With N A D H - T R staining the stored material was surrounded by a linear deposit of formazan. The ATPase reaction showed a predominance of type 1
This 51-yr-old woman had a history of progressive muscle weakness of 10 yr duration. She first noted difficulty in climbing stairs, and then also developed weakness in the arms. On examination, she could not walk on tip-toe or
*Author to whom correspondence should be addressed at: lstituto di Neurologia, Policlinico di B. Roma, 37134 Verona, Italy. 419
420
P. TONINet aL
Fig. I. Fiberscontainingvacuolesof variable sizefilledwith basophilicmaterial. Frozen section, H + E, x 390.
Fig. 2. Large subsareolemmal accumulations and dots of strongly PAS positive material. Frozen section, PAS × 390. fibers (84%). Vacuoles were present in 6% of the fibers; of these 97% belonged to type 1 and only 3% to type 2 fibers. The histochemical stain for phosphorylase was normal, with increased activity in the vacuoles. Two fibers were cytochrome oxidase-negative.
By electron microscopy, the deposits of polysaccharide were not membrane-bound and appeared composed of randomly oriented, unbranched filaments and finely granular material, similar to the amylopeetin-like polyglucosan seen in type IV glycogenosis. Beta
Polyglucosan Body Myopathy
421
Fig. 3. Mass o f unbranched filaments and finely granular material; beta glycogen particles are dispersed among the stored polysaccharide, E.M. x 44,000.
glycogen particles were dispersed among this abnormal material or accumulated at its periphery (Fig. 3). Clusters of normal mitochondria occasionally rimmed the masses. The structure of myofilaments and intramuscular nerve fibers was normal. Biochemical analysis was performed on muscle hom-ogenates. The activity of branching enzyme was measured by a radioactive assay [10], debrancher and phosphofructokinase were studied by a spectrophotometric assay as described in refs [11,12], acid and neutral maltase were measured by a fluorometric assay with the artificial substrate 4-methylumbelliferyl alphaD-glucoside [13]; all activities were normal (see Table 1). The morphological hallmark of this myopathy was a vacuolar accumulation of amylopectin-like polysaccharide closely resembling the polygluc0san found in all tissues in type IV glycogenosis and in the central and peripheral nervous systems in adult-onset polyglucosan body disease (APBD). Since the first description of a myopathy characterized by deposits of abnormal polysaccharide by Holmes et al. [14], 13 more cases have been reported [9]. Although age at onset and course of the disease varied widely, all patients had progressive limb-girdle
Table I. Biochemistry
Acid maltase Neutral maltase Phosphofructokinase Brancher Debrancber
Patient
Control
7.16 10.96 17.74 5.33 5.16
8.03:1:1.48 14.15 :t: 3.13 24.36 ± 5.59 5.68, 4.48, 5.08 3.06 :l: 1.18
Enzyme activities are expressed as gruel urnbelliferone liberated min -~ g-' tissue (acid and neutral maltaso), prnol substrate utilized rain -~ g-' (phosphofructokinase), pmol glucose incorporated (brancber) and liberated (debrancber) min-' g-'.
myopathy. Cardiopathy was also present in six cases. Serum CK was elevated in seven patients; E M G showed a myopathic pattern in all. The clinical picture of our patient was also characterized by late-onset progressive myopathy. Although she had a heart conduction defect, no echocardiogram was performed. There were no signs of peripheral neuropathy or of other organ involvement. Morphological studies of muscle showed deposits of abnormal glycogen both in type 1 and type 2 fibers, with a predominant accumulation of polyglucosan in type 1 fibers, as reported by others [9]. Histochemical staining ruled out phosphorylase deficiency, which may cause late-onset weakness but does not cause accumulation of abnormal polysaccharide [15]. The late onset and proximal distribution of weakness and the vacuolar myopathy, raised
422
P. TONIN et al.
REFERENCES the suspicion of acid maltase deficiency even if this disorder is often accompanied by respiratory insufficiency [I 6]. However, the observation I. Robitaille Y, Carpenter S, Karpati G, Di Mauro S. A distinct form of adult polyglucosan body disease with that the vacuoles were not limited by a memmassive involvement of central and peripheral brane and did not stain for acid phosphatase neuronal processes and astrocytes. A report of four cases and a review of the occurrence of polyglucosan activity made this diagnosis unlikely on bodies in other conditions such as Lafora's disease morphological grounds. Biochemical studies and normal ageing. Brain 1980; 103: 315--336. showing normal acid maltase activity excluded 2. Rosai J, Lascano E F. Basophilic (mucoid) degeneration of the myocardium: a disorder of glycogen metthis possibility. Both histochemical and ultraabolism. Am J Pathol 1970; 61:99-111. structural features of the stored polysaccharide 3. Schochet S S, McCormick W F, Kowarsky J. Light were similar to those of the polyglucosan found and electron microscopy of skeletal muscle in type IV glycogenosis. Acta Neuropathol 1971; 19:137-144. in type IV glycogenosis. Although isolated 4. Ho K L. Basophilic degeneration of skeletal muscle in myopathy can rarely occur in brancher deficihypothyroid myopathy: histochemical and ultrastrucency [17], branching activity was normal in tural studies. Arch Pathol Lab Med 1984; 108: 239-245. 5. McMaster K R, Powers J M, Hennigar G R, et al. muscle from our patient. Phosphofructokinase Nervous system involvement in type IV glycogenosis. deficiency is another possible cause of late-onset Arch Pathol Lab &led 1979; 103:105-111. myopathy associated with amylopectin-like 6. Agamanolis D P, Askari A D, Di Mauro S, et al. Muscle phosphofructokinase deficiency: two cases polyglucosan [7, 8], but this was also excluded with unusual polysaccharide accumulation and in our patient. immunologically active enzyme protein. Muscle Nerve Electron microscopy showed some accumu1980; 3: 456--467. 7. Hays A P, Hallet M, Dells J, et al. Muscle lations of mitochondria, but we did not observe phosphofructokinase deficiency. Abnormal polysacthe intramitochondrial paracrystalline inclucharide in a case of late-onset myopathy. Neurology sions described by others [9]. 1981; 31: 1077-1086. 8. Danon M J, Servidei S, Di Mauro S, Vora S. LateThis case confirms the existence of a distinct onset muscle phosphofructokinase deficiency. clinicopathological entity that can be called Neurology 1988; 38: 956-960. "polyglucosan body myopathy" by analogy to 9. Calore E E, Pellissier J F, Figarella-Branger D, et al. Myopathie par surcharge en polysaccharide de type the adult polyglucosan body disease. amylopectine. Rev Neurol I992; 148: 696-703. Accumulation of polyglucosan in muscle could 10. Servidei S, Riepe R E, Langston C, et aL Severe cardiopathy in branching enzyme deficiency. J Pediatr be the partial expression of a more generalized 1987; 111: 51-56. disorder. Recently, brancher deficiency has 11. Di Mauro S, Hartvig G B, Hays A, et al. Debrancher been associated with polyglucosan body disease deficiency: neuromuscular disorder in five adults. Ann Neurol 1979; 5: 422-436. in two Israeli patients [17] and in two American 12. Layzer R B, Rowland L P, Ranney H M. Muscle patients of Ashkenazy descent [18]. In all four phosphofructokinase deficiency. Arch Neurol 1967; 17: patients, the enzyme defect was documented in 512-523. leukocytes and, in two of them, also in 13. Mehler M, Di Mauro S. Residual acid maltase activity in late-onset acid maltase deficiency. Neurology 1977; peripheral nerves. However, a French Canadian 27: 178-184. patient with adult polyglucosan body disease 14. Holmes J M, Houghton C R, Woolf A L. A myopathy presenting in adult life with features suggestive of had normal enzyme activity in both leukocytes glycogen storage disease. J Neurol Neurosurg Psychand peripheral nerves [19]. These findings iatry 1960; 23:302-31 I. suggest biochemical heterogeneity, i.e. 15. Di Mauro S, Bresolin N. Phosphorylase deficiency. In: Engel A G, Banker B Q, eds. Myology. New York: apparently the same stdrage material can McGraw-Hill, 1986: 1585. accumulate as a consequence of diverse bio- 16. Engel A G. Acid maltase deficiency. In: Engel A G, Banker B Q, eds. Myology. New York: McGraw-Hill, chemical defects. Branching enzyme deficiency 1986: 1629. and phosphofructokinase deficiency can cause 17. Brown B I. Debranching and branching enzyme polyglucosan storage in muscle. The biochemical deficiencies. In: Engel A G, Banker B Q, eds. Myology. New York: McGraw-Hill, 1986: 1653. causes of Lafora disease and polyglucosan body 18. Lossos A, Barash V, Softer D, et aL Hereditary myopathy, however, remain unknown. branching enzyme dysfunction in adult polyglucosan
Acknowledgements---We are grateful to Dr S. Di Mauro for his encouragement and advice. This work was supported by M.U.R.S.T. 40%.
body disease: a possible metabolic cause in two patients. Ann Neurol 1991; 30: 655-662. 19. Bruno C, Servidei S, Shanske S, et al. Glycogen branching enzyme in adult polyglucosan body disease. Neurology 1992; 42 (Suppl 3): 230-231.
0960-8966/92$5.00 + 0.00 01993 PergamonPress Ltd
Printed in Great Britain
CASE REPORT POLYGLUCOSAN
BODY MYOPATHY:
A NEW CASE
P. TONIN,* G. TOMELLERI, M. VIO a n d N. RIZZUTO Institute of Neurology, University of Verona, Verona, Italy
(Received 17 July 1992, revised 26 September 1992, accepted 2 October 1992) Abstract--We report a 51-yr-old woman with late-onset progressive weakness affecting
proximal limb muscles. Muscle biopsy revealed a vacuolar myopathy with accumulation of amylopectin-like polysaccharide resembling the polyglucosan found in type IV glyeogenosis and adult-onset polyglucosan body disease. A biochemical study ruled out specific enzymatic defects known to cause storage of this abnormal material. Our case confirms the existence of a 'polyglucosan body myopathy' as a distinct clinicopathological entity in which the biochemical defect is unknown. Key words: M y o p a t h y , polyglucosan, b r a n c h i n g enzyme.
on heels and was barely able to rise from a squatting position. There was weakness and wasting of proximal limb muscles; the patient was not able to lift her arms up to shoulder level and had a severely reduced abduction. Tendon reflexes were decreased. Sensation was normal. She had slight ptosis, but no dysphagia or dysphonia. There was no parental consanguinity and family history was negative for neuromuscular disorders. Routine blood tests were normal, including CK, aldolase and LDH. Thyroid function was normal. ECG showed incomplete right bundle branch block. The forearm ischemic exercise test was normal. E M G was myopathic and nerve conduction velocity was normal.
INTRODUCTION
Accumulation of a polysaccharide structurally similar to amylopectin has been reported in several disorders mainly affecting the central and peripheral nervous systems [1], but also heart [2], liver [3] and muscle [4]. The etiology in most of these diseases is unknown, but defects of brancher [3, 5] or phosphofruotokinase [6-8] enzymes have been described. Thirteen patients had progressive myopathy, with accumulations of amylopectin-like polysaccharide in muscle, but without known enzymatic defect [9]. We report a new patient with late-onset progressive myopathy and vacuolar deposits of filamentous polyglucosan.
RESULTS AND DISCUSSION CASE REPORT
A biopsy of the vastus la~ralis muscle showed vacuolar myopathy. The vacuoles, which had variable sizes, were located both in the center of the fibers and under the sarcolemma. They contained basophilic (Fig. 1) and strongly PAS-positive material (Fig. 2), which was only partially digested by alpha-amylase. Alcian blue and the stain for acid phosphatase activity were negative. With N A D H - T R staining the stored material was surrounded by a linear deposit of formazan. The ATPase reaction showed a predominance of type 1
This 51-yr-old woman had a history of progressive muscle weakness of 10 yr duration. She first noted difficulty in climbing stairs, and then also developed weakness in the arms. On examination, she could not walk on tip-toe or
*Author to whom correspondence should be addressed at: lstituto di Neurologia, Policlinico di B. Roma, 37134 Verona, Italy. 419
420
P. TONINet aL
Fig. I. Fiberscontainingvacuolesof variable sizefilledwith basophilicmaterial. Frozen section, H + E, x 390.
Fig. 2. Large subsareolemmal accumulations and dots of strongly PAS positive material. Frozen section, PAS × 390. fibers (84%). Vacuoles were present in 6% of the fibers; of these 97% belonged to type 1 and only 3% to type 2 fibers. The histochemical stain for phosphorylase was normal, with increased activity in the vacuoles. Two fibers were cytochrome oxidase-negative.
By electron microscopy, the deposits of polysaccharide were not membrane-bound and appeared composed of randomly oriented, unbranched filaments and finely granular material, similar to the amylopeetin-like polyglucosan seen in type IV glycogenosis. Beta
Polyglucosan Body Myopathy
421
Fig. 3. Mass o f unbranched filaments and finely granular material; beta glycogen particles are dispersed among the stored polysaccharide, E.M. x 44,000.
glycogen particles were dispersed among this abnormal material or accumulated at its periphery (Fig. 3). Clusters of normal mitochondria occasionally rimmed the masses. The structure of myofilaments and intramuscular nerve fibers was normal. Biochemical analysis was performed on muscle hom-ogenates. The activity of branching enzyme was measured by a radioactive assay [10], debrancher and phosphofructokinase were studied by a spectrophotometric assay as described in refs [11,12], acid and neutral maltase were measured by a fluorometric assay with the artificial substrate 4-methylumbelliferyl alphaD-glucoside [13]; all activities were normal (see Table 1). The morphological hallmark of this myopathy was a vacuolar accumulation of amylopectin-like polysaccharide closely resembling the polygluc0san found in all tissues in type IV glycogenosis and in the central and peripheral nervous systems in adult-onset polyglucosan body disease (APBD). Since the first description of a myopathy characterized by deposits of abnormal polysaccharide by Holmes et al. [14], 13 more cases have been reported [9]. Although age at onset and course of the disease varied widely, all patients had progressive limb-girdle
Table I. Biochemistry
Acid maltase Neutral maltase Phosphofructokinase Brancher Debrancber
Patient
Control
7.16 10.96 17.74 5.33 5.16
8.03:1:1.48 14.15 :t: 3.13 24.36 ± 5.59 5.68, 4.48, 5.08 3.06 :l: 1.18
Enzyme activities are expressed as gruel urnbelliferone liberated min -~ g-' tissue (acid and neutral maltaso), prnol substrate utilized rain -~ g-' (phosphofructokinase), pmol glucose incorporated (brancber) and liberated (debrancber) min-' g-'.
myopathy. Cardiopathy was also present in six cases. Serum CK was elevated in seven patients; E M G showed a myopathic pattern in all. The clinical picture of our patient was also characterized by late-onset progressive myopathy. Although she had a heart conduction defect, no echocardiogram was performed. There were no signs of peripheral neuropathy or of other organ involvement. Morphological studies of muscle showed deposits of abnormal glycogen both in type 1 and type 2 fibers, with a predominant accumulation of polyglucosan in type 1 fibers, as reported by others [9]. Histochemical staining ruled out phosphorylase deficiency, which may cause late-onset weakness but does not cause accumulation of abnormal polysaccharide [15]. The late onset and proximal distribution of weakness and the vacuolar myopathy, raised
422
P. TONIN et al.
REFERENCES the suspicion of acid maltase deficiency even if this disorder is often accompanied by respiratory insufficiency [I 6]. However, the observation I. Robitaille Y, Carpenter S, Karpati G, Di Mauro S. A distinct form of adult polyglucosan body disease with that the vacuoles were not limited by a memmassive involvement of central and peripheral brane and did not stain for acid phosphatase neuronal processes and astrocytes. A report of four cases and a review of the occurrence of polyglucosan activity made this diagnosis unlikely on bodies in other conditions such as Lafora's disease morphological grounds. Biochemical studies and normal ageing. Brain 1980; 103: 315--336. showing normal acid maltase activity excluded 2. Rosai J, Lascano E F. Basophilic (mucoid) degeneration of the myocardium: a disorder of glycogen metthis possibility. Both histochemical and ultraabolism. Am J Pathol 1970; 61:99-111. structural features of the stored polysaccharide 3. Schochet S S, McCormick W F, Kowarsky J. Light were similar to those of the polyglucosan found and electron microscopy of skeletal muscle in type IV glycogenosis. Acta Neuropathol 1971; 19:137-144. in type IV glycogenosis. Although isolated 4. Ho K L. Basophilic degeneration of skeletal muscle in myopathy can rarely occur in brancher deficihypothyroid myopathy: histochemical and ultrastrucency [17], branching activity was normal in tural studies. Arch Pathol Lab Med 1984; 108: 239-245. 5. McMaster K R, Powers J M, Hennigar G R, et al. muscle from our patient. Phosphofructokinase Nervous system involvement in type IV glycogenosis. deficiency is another possible cause of late-onset Arch Pathol Lab &led 1979; 103:105-111. myopathy associated with amylopectin-like 6. Agamanolis D P, Askari A D, Di Mauro S, et al. Muscle phosphofructokinase deficiency: two cases polyglucosan [7, 8], but this was also excluded with unusual polysaccharide accumulation and in our patient. immunologically active enzyme protein. Muscle Nerve Electron microscopy showed some accumu1980; 3: 456--467. 7. Hays A P, Hallet M, Dells J, et al. Muscle lations of mitochondria, but we did not observe phosphofructokinase deficiency. Abnormal polysacthe intramitochondrial paracrystalline inclucharide in a case of late-onset myopathy. Neurology sions described by others [9]. 1981; 31: 1077-1086. 8. Danon M J, Servidei S, Di Mauro S, Vora S. LateThis case confirms the existence of a distinct onset muscle phosphofructokinase deficiency. clinicopathological entity that can be called Neurology 1988; 38: 956-960. "polyglucosan body myopathy" by analogy to 9. Calore E E, Pellissier J F, Figarella-Branger D, et al. Myopathie par surcharge en polysaccharide de type the adult polyglucosan body disease. amylopectine. Rev Neurol I992; 148: 696-703. Accumulation of polyglucosan in muscle could 10. Servidei S, Riepe R E, Langston C, et aL Severe cardiopathy in branching enzyme deficiency. J Pediatr be the partial expression of a more generalized 1987; 111: 51-56. disorder. Recently, brancher deficiency has 11. Di Mauro S, Hartvig G B, Hays A, et al. Debrancher been associated with polyglucosan body disease deficiency: neuromuscular disorder in five adults. Ann Neurol 1979; 5: 422-436. in two Israeli patients [17] and in two American 12. Layzer R B, Rowland L P, Ranney H M. Muscle patients of Ashkenazy descent [18]. In all four phosphofructokinase deficiency. Arch Neurol 1967; 17: patients, the enzyme defect was documented in 512-523. leukocytes and, in two of them, also in 13. Mehler M, Di Mauro S. Residual acid maltase activity in late-onset acid maltase deficiency. Neurology 1977; peripheral nerves. However, a French Canadian 27: 178-184. patient with adult polyglucosan body disease 14. Holmes J M, Houghton C R, Woolf A L. A myopathy presenting in adult life with features suggestive of had normal enzyme activity in both leukocytes glycogen storage disease. J Neurol Neurosurg Psychand peripheral nerves [19]. These findings iatry 1960; 23:302-31 I. suggest biochemical heterogeneity, i.e. 15. Di Mauro S, Bresolin N. Phosphorylase deficiency. In: Engel A G, Banker B Q, eds. Myology. New York: apparently the same stdrage material can McGraw-Hill, 1986: 1585. accumulate as a consequence of diverse bio- 16. Engel A G. Acid maltase deficiency. In: Engel A G, Banker B Q, eds. Myology. New York: McGraw-Hill, chemical defects. Branching enzyme deficiency 1986: 1629. and phosphofructokinase deficiency can cause 17. Brown B I. Debranching and branching enzyme polyglucosan storage in muscle. The biochemical deficiencies. In: Engel A G, Banker B Q, eds. Myology. New York: McGraw-Hill, 1986: 1653. causes of Lafora disease and polyglucosan body 18. Lossos A, Barash V, Softer D, et aL Hereditary myopathy, however, remain unknown. branching enzyme dysfunction in adult polyglucosan
Acknowledgements---We are grateful to Dr S. Di Mauro for his encouragement and advice. This work was supported by M.U.R.S.T. 40%.
body disease: a possible metabolic cause in two patients. Ann Neurol 1991; 30: 655-662. 19. Bruno C, Servidei S, Shanske S, et al. Glycogen branching enzyme in adult polyglucosan body disease. Neurology 1992; 42 (Suppl 3): 230-231.