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Case Reports / Journal of Clinical Neuroscience 22 (2015) 1674–1675
[4] Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome: definitions and longterm outcome. Blood 2003;101:2496–506. [5] Cui R, Yu S, Huang X, et al. Papilloedema is an independent prognostic factor for POEMS syndrome. J Neurol 2014;261:60–5. [6] Kuwabara S, Dispenzieri A, Arimura K, et al. Treatment for POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome. Cochrane Database Syst Rev 2008:CD006828. [7] Scarlato M, Previtali SC, Carpo M, et al. Polyneuropathy in POEMS syndrome: role of angiogenic factors in the pathogenesis. Brain 2005;128: 1911–20.
[8] Dispenzieri A. POEMS syndrome: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol 2014;89:214–23. [9] Kaushik M, Pulido JS, Abreu R, et al. Ocular findings in patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome. Ophthalmology 2011;118: 778–82. [10] Bourdette DN, Rosenberg NL. Infiltrative orbitopathy, optic disk edema, and POEMS. Neurology 1984;34:532–3. [11] Dispenzieri A. How I treat POEMS syndrome. Blood 2012;119:5650–8.
http://dx.doi.org/10.1016/j.jocn.2015.03.041
Pathological characteristics of glycogen storage disease III in skeletal muscle Leah D. Gershen b, Brigid E. Prayson c, Richard A. Prayson a,⇑ a
Department of Anatomic Pathology, Cleveland Clinic, Level 25, 9500 Euclid Avenue, Cleveland, OH 44195, USA Lerner College of Medicine, Cleveland Clinic, Case Western Reserve University, Cleveland, OH, USA c John Carroll University, Cleveland, OH, USA b
a r t i c l e
i n f o
Article history: Received 2 March 2015 Accepted 7 March 2015
Keywords: Cori disease Debrancher enzyme deficiency Glycogenosis III Skeletal muscle biopsy
a b s t r a c t We report a 25-year-old man with glycogenosis III who presented with a progressive 2 year history of fatigue, hand stiffness and cramping. The glycogenoses are a group of rare metabolic disorders which develop as a result of deficiencies in various enzymes involved in the metabolism of glycogen. Some, but not all, glycogenoses, may result in skeletal muscle pathology. Among those that result in vacuolar myopathic changes, glycogen storage disease III or debrancher enzyme deficiency, an autosomal recessive condition, is less commonly encountered than acid maltase (Type II) and myophosphorylase (Type V) deficiencies. Many patients with debrancher enzyme deficiency also have liver involvement. The neurological examination of our patient showed mild proximal limb weakness and decreased reflexes. He had elevated creatine kinase and aldolase levels. He also demonstrated some elevations in his liver function tests, suggesting possible liver involvement. A skeletal muscle biopsy demonstrated vacuolar myopathic changes (acid phosphatase negative) accompanied by focal endomysial fibrosis and chronic inflammation. An ultrastructural examination showed that his vacuoles were filled with glycogen material. An enzyme assay of skeletal muscle tissue showed a significant decrease in debrancher enzyme activity (11% of normal). We review the typical clinical presentation of patients with glycogenosis III and discuss the differential diagnoses of glycogenosis III versus the other glycogenoses resulting in vacuolar myopathy. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction Several of the hereditary enzyme deficiencies in the glycogen metabolic pathway cause vacuolar myopathies associated with glycogen storage disease (GSD). Glycogen storage disease III (GSD III; Cori disease) is an autosomal recessive deficiency of the glycogen debrancher enzyme (amylo-1,6-glucosidase) that results in the accumulation of abnormal glycogen [1]. Affected patients often develop myopathy later in life, including cardiomyopathy, and typically present with hepatomegaly, hypoglycemia and delayed growth in childhood. We report a man with debrancher enzyme deficiency isolated to skeletal muscle, with normal enzyme activity in his liver.
2. Case report A 25-year-old Caucasian man presented with a 2 year history of progressive generalized fatigue, as well as hand stiffness and
⇑ Corresponding author. Tel.: +1 216 444 8805; fax: +1 216 445 6967. E-mail address: [email protected] (R.A. Prayson).
cramping with repetitive movements. He also experienced chest pain and noted dark urine in the mornings. His neurological examination revealed normal muscle bulk and tone, but mild proximal limb muscle weakness which was worse in the legs than arms. His reflexes were 1/4 throughout. A laboratory evaluation revealed elevated serum creatinine kinase (3261 U/L), aldolase (30.5 U/L), and liver enzymes (aspartate transaminase 225 U/L; alanine transaminase 290 U/L). His bilirubin, electrolytes, and fasting glucose were normal. A urinalysis showed elevated protein and ketones, but no bilirubin or blood. An extensive cardiac workup was normal and the cause of his chest pain was not identified. A biopsy of the left tibialis anterior muscle showed moderate variation in muscle fiber size with focal increased endomysial fibrosis, focal chronic endomysial inflammation, and vacuoles in scattered muscle fibers (Fig. 1). Many of the vacuoles were subsarcolemmally positioned, did not stain with acid phosphatase (Fig. 2), and demonstrated increased periodic acid Schiff staining. There were no abnormalities in myophosphorylase staining observed. Electron microscopic examination of the muscle confirmed that the vacuoles were filled with glycogen material (Fig. 3). Tissue assays for glycogen pathway-associated enzymes
Case Reports / Journal of Clinical Neuroscience 22 (2015) 1674–1675
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Fig. 1. Scattered muscle fibers showed subsarcolemmal vacuoles (arrows; hematoxylin and eosin; original magnification 200).
Fig. 3. Ultrastructural examination of the muscle showed large granular glycogen deposits (arrows; original magnification 3600).
Fig. 2. Acid phosphatase staining was not observed in association with the vacuoles, ruling out a deficiency in lysosomal-associated acid maltase (glycogenoses type II; original magnification 200).
showed that the debrancher enzyme was markedly deficient (11% of normal) in muscle tissue, but was normal in the liver.
The main differential diagnoses for GSD III are the other glycogen storage diseases. Glycogen storage diseases that affect skeletal muscle include GSD IIIa, late onset Pompe disease (GSD II; acid maltase deficiency), McArdle’s disease (GSD V; muscle phosphorylase deficiency), and the neuromuscular form of GSD IX (phosphorylase kinase deficiency). All of these diseases present with increased glycogen in the muscles and elevated serum creatinine kinase. GSD II often affects the diaphragm but does not affect the liver. Exertional muscle cramping and stiffness are usually distinguishing features of GSD V and VII, but were seen in our patient with GSD III. In addition to differences in clinical presentation, histopathologic differences can help to distinguish the glycogenoses. Whereas most GSD are characterized by excessive accumulation of normal glycogen, GSD III results in the accumulation of abnormally structured glycogen with shorter outer branches (decreased glucose-1-phosphate to glucose ratio). GSD III may also have a lipid component in the vacuoles. In GSD II, glycogen stores tend to be membrane-bound lysosomal vacuoles (acid phosphatase positive) rather than cytoplasmic, as in GSD III.
3. Discussion
Conflicts of Interest/Disclosures
The clinical presentation of GSD III varies widely in terms of the severity and affected tissue types. The debrancher enzyme is typically deficient in both liver and muscle tissue (GSD IIIa). Less commonly, the deficiency can be restricted to the liver (GSD IIIb). However, debrancher enzyme deficiency is almost never restricted to muscle, with only a few reported patients in the literature [2]. Our patient had no history of significant liver dysfunction at presentation or in childhood other than mild elevations in liver enzymes.
The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
http://dx.doi.org/10.1016/j.jocn.2015.03.041
References [1] Kishnani PS, Austin SL, Arn P, et al. Glycogen storage disease type III diagnosis and management guidelines. Genet Med 2010;12:446–63. [2] Momoi T, Sano H, Yamanaka C, et al. Glycogen storage disease type III with muscle involvement: reappraisal of phenotypic variability and prognosis. Am J Med Genet 1992;42:696–9.
Case Reports / Journal of Clinical Neuroscience 22 (2015) 1674–1675
[4] Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome: definitions and longterm outcome. Blood 2003;101:2496–506. [5] Cui R, Yu S, Huang X, et al. Papilloedema is an independent prognostic factor for POEMS syndrome. J Neurol 2014;261:60–5. [6] Kuwabara S, Dispenzieri A, Arimura K, et al. Treatment for POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome. Cochrane Database Syst Rev 2008:CD006828. [7] Scarlato M, Previtali SC, Carpo M, et al. Polyneuropathy in POEMS syndrome: role of angiogenic factors in the pathogenesis. Brain 2005;128: 1911–20.
[8] Dispenzieri A. POEMS syndrome: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol 2014;89:214–23. [9] Kaushik M, Pulido JS, Abreu R, et al. Ocular findings in patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome. Ophthalmology 2011;118: 778–82. [10] Bourdette DN, Rosenberg NL. Infiltrative orbitopathy, optic disk edema, and POEMS. Neurology 1984;34:532–3. [11] Dispenzieri A. How I treat POEMS syndrome. Blood 2012;119:5650–8.
http://dx.doi.org/10.1016/j.jocn.2015.03.041
Pathological characteristics of glycogen storage disease III in skeletal muscle Leah D. Gershen b, Brigid E. Prayson c, Richard A. Prayson a,⇑ a
Department of Anatomic Pathology, Cleveland Clinic, Level 25, 9500 Euclid Avenue, Cleveland, OH 44195, USA Lerner College of Medicine, Cleveland Clinic, Case Western Reserve University, Cleveland, OH, USA c John Carroll University, Cleveland, OH, USA b
a r t i c l e
i n f o
Article history: Received 2 March 2015 Accepted 7 March 2015
Keywords: Cori disease Debrancher enzyme deficiency Glycogenosis III Skeletal muscle biopsy
a b s t r a c t We report a 25-year-old man with glycogenosis III who presented with a progressive 2 year history of fatigue, hand stiffness and cramping. The glycogenoses are a group of rare metabolic disorders which develop as a result of deficiencies in various enzymes involved in the metabolism of glycogen. Some, but not all, glycogenoses, may result in skeletal muscle pathology. Among those that result in vacuolar myopathic changes, glycogen storage disease III or debrancher enzyme deficiency, an autosomal recessive condition, is less commonly encountered than acid maltase (Type II) and myophosphorylase (Type V) deficiencies. Many patients with debrancher enzyme deficiency also have liver involvement. The neurological examination of our patient showed mild proximal limb weakness and decreased reflexes. He had elevated creatine kinase and aldolase levels. He also demonstrated some elevations in his liver function tests, suggesting possible liver involvement. A skeletal muscle biopsy demonstrated vacuolar myopathic changes (acid phosphatase negative) accompanied by focal endomysial fibrosis and chronic inflammation. An ultrastructural examination showed that his vacuoles were filled with glycogen material. An enzyme assay of skeletal muscle tissue showed a significant decrease in debrancher enzyme activity (11% of normal). We review the typical clinical presentation of patients with glycogenosis III and discuss the differential diagnoses of glycogenosis III versus the other glycogenoses resulting in vacuolar myopathy. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction Several of the hereditary enzyme deficiencies in the glycogen metabolic pathway cause vacuolar myopathies associated with glycogen storage disease (GSD). Glycogen storage disease III (GSD III; Cori disease) is an autosomal recessive deficiency of the glycogen debrancher enzyme (amylo-1,6-glucosidase) that results in the accumulation of abnormal glycogen [1]. Affected patients often develop myopathy later in life, including cardiomyopathy, and typically present with hepatomegaly, hypoglycemia and delayed growth in childhood. We report a man with debrancher enzyme deficiency isolated to skeletal muscle, with normal enzyme activity in his liver.
2. Case report A 25-year-old Caucasian man presented with a 2 year history of progressive generalized fatigue, as well as hand stiffness and
⇑ Corresponding author. Tel.: +1 216 444 8805; fax: +1 216 445 6967. E-mail address: [email protected] (R.A. Prayson).
cramping with repetitive movements. He also experienced chest pain and noted dark urine in the mornings. His neurological examination revealed normal muscle bulk and tone, but mild proximal limb muscle weakness which was worse in the legs than arms. His reflexes were 1/4 throughout. A laboratory evaluation revealed elevated serum creatinine kinase (3261 U/L), aldolase (30.5 U/L), and liver enzymes (aspartate transaminase 225 U/L; alanine transaminase 290 U/L). His bilirubin, electrolytes, and fasting glucose were normal. A urinalysis showed elevated protein and ketones, but no bilirubin or blood. An extensive cardiac workup was normal and the cause of his chest pain was not identified. A biopsy of the left tibialis anterior muscle showed moderate variation in muscle fiber size with focal increased endomysial fibrosis, focal chronic endomysial inflammation, and vacuoles in scattered muscle fibers (Fig. 1). Many of the vacuoles were subsarcolemmally positioned, did not stain with acid phosphatase (Fig. 2), and demonstrated increased periodic acid Schiff staining. There were no abnormalities in myophosphorylase staining observed. Electron microscopic examination of the muscle confirmed that the vacuoles were filled with glycogen material (Fig. 3). Tissue assays for glycogen pathway-associated enzymes
Case Reports / Journal of Clinical Neuroscience 22 (2015) 1674–1675
1675
Fig. 1. Scattered muscle fibers showed subsarcolemmal vacuoles (arrows; hematoxylin and eosin; original magnification 200).
Fig. 3. Ultrastructural examination of the muscle showed large granular glycogen deposits (arrows; original magnification 3600).
Fig. 2. Acid phosphatase staining was not observed in association with the vacuoles, ruling out a deficiency in lysosomal-associated acid maltase (glycogenoses type II; original magnification 200).
showed that the debrancher enzyme was markedly deficient (11% of normal) in muscle tissue, but was normal in the liver.
The main differential diagnoses for GSD III are the other glycogen storage diseases. Glycogen storage diseases that affect skeletal muscle include GSD IIIa, late onset Pompe disease (GSD II; acid maltase deficiency), McArdle’s disease (GSD V; muscle phosphorylase deficiency), and the neuromuscular form of GSD IX (phosphorylase kinase deficiency). All of these diseases present with increased glycogen in the muscles and elevated serum creatinine kinase. GSD II often affects the diaphragm but does not affect the liver. Exertional muscle cramping and stiffness are usually distinguishing features of GSD V and VII, but were seen in our patient with GSD III. In addition to differences in clinical presentation, histopathologic differences can help to distinguish the glycogenoses. Whereas most GSD are characterized by excessive accumulation of normal glycogen, GSD III results in the accumulation of abnormally structured glycogen with shorter outer branches (decreased glucose-1-phosphate to glucose ratio). GSD III may also have a lipid component in the vacuoles. In GSD II, glycogen stores tend to be membrane-bound lysosomal vacuoles (acid phosphatase positive) rather than cytoplasmic, as in GSD III.
3. Discussion
Conflicts of Interest/Disclosures
The clinical presentation of GSD III varies widely in terms of the severity and affected tissue types. The debrancher enzyme is typically deficient in both liver and muscle tissue (GSD IIIa). Less commonly, the deficiency can be restricted to the liver (GSD IIIb). However, debrancher enzyme deficiency is almost never restricted to muscle, with only a few reported patients in the literature [2]. Our patient had no history of significant liver dysfunction at presentation or in childhood other than mild elevations in liver enzymes.
The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
http://dx.doi.org/10.1016/j.jocn.2015.03.041
References [1] Kishnani PS, Austin SL, Arn P, et al. Glycogen storage disease type III diagnosis and management guidelines. Genet Med 2010;12:446–63. [2] Momoi T, Sano H, Yamanaka C, et al. Glycogen storage disease type III with muscle involvement: reappraisal of phenotypic variability and prognosis. Am J Med Genet 1992;42:696–9.
