Glycogen Storage Disease: Clinical, Biochemical, and Molecular Heterogeneity Yoon S. Shin, PhD

Glycogen storage diseases (GSDs) are characterized by abnormal inherited glycogen metabolism in the liver, muscle, and brain and divided into types 0 to X. GSD type I, glucose 6-phosphatase system, has types Ia, Ib, Ic, and Id, glucose 6-phosphatase, glucose 6-phosphate translocase, pyrophosphate translocase, and glucose translocase deficien- cies, respectively. GSD type II is caused by defective lysosomal ␣-glucosidase (GAA), subdivided into 4 onset forms. GSD type III, amylo-1,6-glucosidase deficiency, is subdi- vided into 6 forms. GSD type IV, Andersen disease or amylopectinosis, is caused by deficiency of the glycogen-branching enzyme in numerous forms. GSD type V, McArdle disease or muscle phosphorylase deficiency, is divided into 2 forms. GSD type VI is characterized by liver phosphorylase deficiency. GSD type VII, phosphofructokinase defi- ciency, has 2 subtypes. GSD types VIa, VIII, IX, or X are supposedly caused by tissue- specific phosphorylase kinase deficiency. GSD type 0, glycogen synthase deficiency, is divided into 2 subtypes. Semin Pediatr Neurol 13:115-120 © 2006 Elsevier Inc. All rights reserved.

KEYWORDS Glycogen storage disease, acid maltase, debranching enzyme, branching enzyme, phosphorylase, phosphofructokinase

lycogen storage disease (GSD), inborn errors of glyco- sion, and platelet dysfunction. The microsomal G6Pase system Ggen metabolism, has been known to mainly be a liver consists of membrane-bound phosphohydrolase and various disease with the exception of Pompe (GSD type II), McArdle translocases for G6P (T1), phosphate (T2), and glucose (T3).2,3 (GSD type V), or Tarui (GSD type VII) diseases. Recently, Deficiency of T1, namely GSD type Ib, shows systemic infec- however, various muscular disorders involving different tions like stomatitis, Crohn-like enteritis as a result of neutrope- types of muscles have been described to be caused by defec- nia, neutrophil, and monocyte dysfunction. Common labora- tive glycogen metabolism. The respective deficient enzymes tory findings of GSD Ia and Ib are hypoglycemia, and the responsible genes of various GSD types are com- hyperlipidemia, hyperuricemia, and lactic acidemia. Deficien- prised in Tables 1 and 2. cies of T2 (GSD Ic) or T3 (GSD Id) have not yet been completely elucidated; however, the patients are supposed to have milder GSD Type I (von Gierke Disease) clinical courses.3,4 As an initial diagnostic step for GSD I, the glucagon and epinephrine loading test can support the clinical Glucose 6-phosphatase (G6Pase), the key enzyme in the ho- suspicion. Through the observation of a significant elevation of meostatic regulation of blood glucose levels, catalyzes the termi- plasma biotinidase among patients with GSD Ia,5 we have de- nal step in both glycogenolysis and gluconeogenesis.1 Defi- veloped a 2-step diagnostic procedure without liver biopsy to ciency of G6Pase, the most severe form of hepatic GSDs, is confirm the clinical diagnosis of GSD Ia: the plasma biotinidase characterized by hepatomegaly, nephromegaly, obesity, tachy- assay followed by the molecular analysis of the G6Pase gene.6 pnea, and short stature. Chronic complications are hepatic ad- According to our data of over 50 GSD type Ia patients, R83C and enomas, gout, osteoporosis, renal failure, pulmonary hyperten- Q347X account for approximately 60% among the white pop- ulation. For the diagnosis of GSD Ib, the analysis of a fresh liver sample is necessary.4 However, this can be spared by the analy- University Childrens’ Hospital and Molecular Genetics and Metabolism Lab- sis of the glucose transport in polymorphonuclear cells7,8 fol- oratory, Munich, Germany. 9 Address reprint requests to Yoon S. Shin, PhD, Molecular Genetics and lowed by the G6PT gene analysis. According to our experience Metabolism Laboratory, Theresienstrasse 29, 80333 Munich, Germany. and other reports, mutations c1211 to 1212 delCT, G339C, and E-mail: [email protected] 1 bp insertion account for approximately 33%, 20%, and 10%

1071-9091/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. 115 doi:10.1016/j.spen.2006.06.007 116 Y.S. Shin

Table 1 Various Types of Glycogen Storage Disease Types I-IV Type Deficient enzyme Gene symbol Literature I (von Gierke) Ia Glucose 6-phophatase G6PC 6 Ib G6P tranlocase (T1) SLC37A4 9 Ic Phophotranslocase (T2) NPT4(?) 10,11 Id Glucose translocase (T3) ? II Infantile (Pompe disease) Lysosomal ␣-glucosidase GAA 17 Childhood ؆؆؆ Juvenile ؆؆؆ Adult ؆؆؆ III (Cori disease) IIIa (Liver & muscle form) Amylo-1,6-glucosidase AGL 24 IIIb (liver form) ؆؆؆ IIIc (muscle form) ؆؆؆ IV (Andersen disease) Infantile form Branching enzyme GBE1 37,38 Liver) Branching enzyme ؆؆) Neuomuscular) ؆؆؆) Juvenile or adult form (Liver, muscle) ؆؆؆ Polyglucosan body disease (APBD) ؆؆؆ alleles, respectively, among white GSD Ib patients.10 The molec- involved. The late-onset form shows slower progression of my- ular defect of GSD Ic has not yet been clearly elucidated.11,12 opathy than the infantile onset form and seldom cardiomegaly. The juvenile/adult forms reveal predominant slowly progressing GSD Type II proximal muscular weakness in lower extremities with truncal involvement and sometimes respiratory insufficiency.13,14 The Patients with the infantile form of lysosomal 1,4-␣-glucosidase GAA activity in muscle or in fibroblasts correlates inversely with deficiency or Pompe disease start to show clinical symptoms at a clinical subtypes, the infantile form having less than 2%, child- median age of 1.6 months. They usually present within 6 hood 1% to 5%, and juvenile and adult up to 22% residual months of life with severe axial hypotonia, hypertrophic cardio- enzyme activities. According to the Rotterdam group, the GAA myopathy, respiratory insufficiency, frequent respiratory infec- activity in fibroblasts is significantly influenced by culture tech- tions, delayed motor milestones, hepatomegaly, and macroglos- niques such as culture duration.15 Thus, special caution is nec- sia. The symptoms of the childhood forms are severely essary for detecting late-onset forms with this kind of cell type.15 progressive with predominantly proximal muscular weakness Even though the early-onset forms can easily be diagnosed in involving also respiratory muscles, but cardiac muscle is rarely leukocytes,16 a secure diagnosis of the late-onset forms can be

Table 2 Various Types of Glycogen Storage Disease Types V-X and 0 Type Deficient enzyme Gene symbol Literature V (McArdle disease) Adult form Muscle phosphorylase PYGM 40 Infantile form ؆؆؆ VI (Hers disease) Liver phosphorylase PYGL 41 VII (Tarui disease) Severe form Phosphofructokinase PFKM 42 Mild form ؆؆؆ Phosphorylase activation system defects VIII (VIa/IXA) Phosphorylase kinase (liver PBK) (XLG I/II) ␣-subunit of PBK PHKA2 46-48 Autosomal recessive ␤ subunit of PBK PHKB 47,49 IXB ␥ or ␦ subunit of PBK (?) PHKG2 50,52 IXC Cardiac muscle PBK ? IXD (adult form) Muscle PBK PHKA1 51 (Severe muscle form) PHKA1(?), PHKG1(?) 51,52 X (multisystem) Protein kinase(?) ? GSD 0 Glycogen synthase (liver) GYS2 53 ؆ (muscle) GYS1 54 Glycogen storage disease 117 made by analysis of other tissues or by the molecular study of the Table 4 Mutation Patterns of 22 Patients With Childhood and GAA gene.17 Recently, a simple procedure for detection of late- Late-Onset GSD II in Germany* onset forms using leukocytes, glycogen, and a potent inhibitor Childhood form for matose glycoamylase, namely acarbose, has been devel- IVS1-13T>G/? IVS1-13T>G/ oped.15,18 The Argentinian group reported the possible screen- c.1703A>T/c.2014C>T IVS1-13T>G/c.1564 G>A ing method of GSD II with filter paper by using the fluorescence IVS1-13T>G/c.118C>T IVS1-13T>G/IVS18-2A>G substrate and acarbose.19 We have applied the fluorometric as- Juvenile form say at 2 pHs applying acarbose and found positive results that IVS1-13T>G/? IVS1-13T>G/c.1548G>A could enable us to diagnose the late-onset forms securely with- IVS1-13T>G/c.1802C>T IVS1-13T>G/del exon 18 IVS1-13T>G/c.1064T>C IVS1-13T>G/del exon 18 out biopsies. Screening of the 3 common mutations, 525delT, Ͼ Adult form del Exon 18, and IVS1 to 13T G, covers approximately 60% of IVS1-13T>G/del exon 18 IVS1-13T>G/IVS6-2A>G the GAA alleles among patients of Northern-European ori- c.271G>A/c.271G>A c.719C>T/c.877G>A 13,14,20 Ͼ gin (Tables 3 and 4). Especially the IVS1 to 13T G mu- c.923 A>T/? IVS1-13T>G/525delT tation, newly renamed as c.-32 to 13TϾG, is closely related to IVS1-13T>G/525delT IVS1-13T>G/IVS1- the late-onset forms13–15,20,21 (Table 3). We describe here an 13TT>G interesting case of premature cerebral angiopathy in a 30-year- IVS1-13T>G/c.1364- IVS1-13T>G/c.1364-1369 old woman with a 4-year history of proximal muscle weakness 3169delG delgfsTer476 with an elevated creatine kinase (CK) who was otherwise *Data provided by T. Podskarbi, Munich, Germany. healthy and had no other complaints. Histologic and biochem- ical investigations of muscle biopsy showed vacuolar myopathy in up to 70% of the myofibers, a distinctly low-acid alpha- tivity, glycogen accumulation, CK elevation, organ involvement, glucosidase activity and an elevated glycogen content. and disease progression. Furthermore, distinctions between ear- Genomic analysis revealed compound heterozygosity for ly-onset and late-onset forms do reflect differences in their pri- c.719CϾT(Ala237Val) and c.877GϾA (Gly293Arg). A few mary molecular pathogenesis, conditions previously separated months after the diagnosis, she complained of numbness of the on grounds of clinical symptoms, muscle histology, and activity left part of her face and left arm, which lasted for 2 to 3 hours measurement. As shown in Table 4, the data of mutation status followed by bilateral frontal headache almost every three weeks. among 45 German and Turkish patients in Germany, the -32 to The emergency computerized cranial tomography (CCT) scan 13AϾG mutation is the most prevalent mutation especially of after the third episode revealed dilative angiopathy of the intra- late-onset forms. cerebral vessels especially of the basilar artery. Doppler ultrasound investigation showed flow reduction in GSD Type III (Cori Disease) the basilary artery, in the intracranial carotid artery, and in the anterior cerebral artery. Magnetic resonance angiography also Cori disease, characterized by amylo-1,6-glucosidase (AGL, de- showed a relative stenosis of the middle cerebral artery, and T2w branching enzyme) deficiency, also divided into several sub- magnetic resonance imaging scans showed singular white-mat- groups; IIIa is defined as a liver and muscle form, IIIb an isolated ter lesions. This indicates that the 3-level clinical subtype classi- liver form, and IIIc an isolated muscle form. Laboratory param- fication does not fully take into account the heterogeneous spec- trum of GAA phenotypes. A correlation of various forms, however, can be made with underlying mutations, enzyme ac- Table 5 The AGL Activity and Mutations in the AGL Gene in GSD III Patients* AGL activity Table 3 Mutation Patterns of 23 Patients with GSD II (Pompe Subtypes in red cells† Mutations Disease) in Germany* IIIa (typical form) 0 R408X, L124X, 587delC, Infantile form 4529insA ,c.1859G>A/del Exon 18 c.525delT/del Exon 18 ؆ 0 4234delA, 3964delT c.525delT/c.525delT c.525delT/c.525delT 4455delT c.525delT/c.1933G>A IVS3؉2T>C/del Exon 18 ؆ 0 4216-4217delAG, 2072- c.1829C>T/c.1912G>A del exon 18/? 2073insA ,c.1561G>A/? c.525delT/1127–1130delG ؆ 0 G1448R, IVS29-1G>C IVS1-13T>G/c.2214G>A c.1655T>C/c.1050–1051delG IVS14؉1G>T c.896T>C/c.896T>C IVS11-2A>G/IVS11-2A>G Egyptians (IIIa)‡ 0 del Exon 7, W1327X, c.2741insC2743insG؉/؉ c.2741insC2743insG؉/؉ del Exon 21 c.1064T>C/c.2303C>G c.915G>A/c.915G>A IIIa (mild form) 0.05 IVS32-12A> c.1064T>C/c.2741ins c.2741insC2743insG؉/؉ IIIb 0.02-0.05 Q6X, 17delAG, R864X C2743insG ؆؆R1228X, W680X IVS19-3C>G/IVS19- IVS1-13T>G/1050- IIId 0.15-0.25 delExon11 3C>G 1051delgfsTer391 *www.hgmd.org. c.1933G>A/? †In nmol/min/g Hb; normal range: 0.6 to 3.5. *Data provided by T. Podskarbi, Munich, Germany. ‡Literature 25. 118 Y.S. Shin eters and clinical symptoms include mild hypoglycemia, lactic Table 6 Clinical, Biochemical, and Molecular Aspects of acidemia, CK elevation, hepatosplenomegaly, muscular hy- Andersen Disease* potonia, and sometimes cardiomegaly. Through measuring GBE activity in the debranching enzyme activity in red cells determined by Form leukocytes† Mutations the glucose incorporation into glycogen, one can easily dis- Classic hepatic form 0 R515C tinguish various forms: IIIa 0%, IIIb 0% to 5%, IIIc 20% to 0 F257L 30%, and IIId (isolated transferase deficiency) 30% to 50% 0 R524X residual enzyme activity22,23 (Table 5). The AGL gene is lo- 0 R515H cated on chromosome 1p21 and consists of 35 exons span- Non progressive 0.01-0.025 Y329S ning more than 85kb, mRNA consisting of a 4596-bp coding hepatic form ؆ R524Q region, and 12,371-bp 3= nontranslated region.24 Gene anal- (juvenile form) ؆ IVS5؉2T>C ؆ ysis of Egyptian patients with GSD IIIa shows several preva- L224P lent mutations in the AGL gene, del. Exon 7, W1327X and Neuromuscular 0 deletion of 210 bp neonatal form del. Exon 21, but among whites with GSD IIIa or IIIb, muta- Adult polyglucosan 0.01-0.025 R524Q 25,26 tions spread throughout the whole gene (Table 5). Fur- body disease ؆ Y329S thermore, mutations in the AGL gene among patients with (APBD) GSD IIIc, the muscular form, have not been reported until *Molecular data provided by Dres. T. Podskarbi and M. Vorgerd, now. As shown in Table 5, mutations in the AGL gene among Germany. white patients are extremely heterogeneous except in Egyp- †Allele activity in nmol/min/mg protein; normal range: 0.1 to 0.5. tian and Japanese patients.25,26

GSD Type IV determining the enzyme activity in cultivated amniotic cells or chorionic villous samplings as well as by GBE gene analy- (Andersen Disease) sis.37 The human GBE1 gene is localized on chromosome Andersen disease characterized by deficiency of ␣-1,4-glucan: 3p14 and consists of 16 exons, about 118 kb chromosomal ␣-1,4glucan 6-transglucosylase (branching enzyme, GBE 1) is DNA.37,38 In the classic hepatic form with rapid progressive presently divided into multiple subgroups as well including liver cirrhosis in childhood, 3 mutations, R515C, F257L, and classic liver form, mild nonprogressive liver form, infantile neu- R524X, were identified; in the mild nonprogressive hepatic romuscular form, adulthood muscular form, juvenile liver and form L224P, Y329S, IVS5 ϩ 2TϾC, and R515H mutations; muscular form, adult polyglucosan body disease (APBD), and in the neuromuscular neonatal form deletion of 210 bp; and generalized severe fatal form.27–35 Clinical manifestation of GSD in APBD several missense mutations such as R515H, R524Q, IV is as expected accordingly variable. The classic form, a severe and Y329S were identified.32,38 In Table 6 we have comprised liver form, is characterized by hepatosplenomegaly and progres- biochemical and molecular data of multiple subtypes. sive hepatic fibrosis during the first 18 months of life. Patients with a rare nonprogressive mild liver form do not develop cir- GSD Types V rhosis and survive until adulthood. Patients with the infantile neuromuscular form may present at birth with severe hypoto- and VI (McArdle nia, muscular atrophy, and neuronal involvement resulting in Disease and Hers Disease) death during the neonatal period. A severe multisystemic neo- natal form presents hydrops fetalis in addition to severe organ Phosphorylase deficiency is divided into 2 major groups: the damages. A juvenile muscular form presents mainly with my- muscular form (McArdle disease, GSD V) and the liver form opathy but sometimes accompanies cardiomyopathy. APBD, a (Hers disease, GSD VI). For GSD type V patients, the biochem- late-onset neuroform, is characterized by central and peripheral ical diagnosis is usually made by measuring the enzyme activity nervous system dysfunction and presents progressive motor (PYGM) and the glycogen content in muscle because the en- neuron signs, sensory loss, urinary dysfunction, dementia, and zyme in leukocytes consists mostly of the liver isozyme (PYGL). rare cardiomyopathy in adulthood. An isolated adult skeletal Two types of GSD V have been so far described: a severe infantile muscular form shows principally exercise intolerance.27 Histo- form with respiratory failure and a mild adult form with exercise intolerance.39 The confirmation of the diagnosis can be made by logic investigation with electronmicroscopy of APBD patients 40,41 reveals positive periodic acid-Schiff (PAS) and diastase-resistant the respective PYGM or PYGL gene analysis. inclusions with amylopectin-like material.27,29–31 The branching enzyme activity is deficient in leukocytes, Phosphofruktokinase liver, and cultured fibroblasts of the neonatal and infantile Deficiency (GSD VII) liver forms as well as of the cardiac form.31,36 About 10% residual activity was found in leukocytes among patients with Tarui disease is also divided into 2 groups: the severe infantile APBD and the mild liver forms.29–30,32 Isolated muscle forms form with respiratory failure and the mild adult form with of GSD IV, on the other hand, show the low GBE activity in exercise intolerance. Both show hemolysis, hyperuricemia, skeletal muscle only.27,33 Prenatal diagnosis is possible by and myoglobinuria. Even though red cells can be used for the Glycogen storage disease 119

Table 7 Diagnostic Possibilities of Various GSDs Type Enzyme assay Carrier detection Prenatal diagnosis Ia Liver DNA DNA Ib Liver, PMN PMN(?), DNA ؆ II WBC, muscle WBC(?), DNA CVS, AFC, DNA III RBC, tissues RBC, DNA ؆ IV WBC, tissues WBC, DNA ؆ V Muscle DNA ؆ VI WBC, liver DNA DNA VII Blood(?), muscle DNA ؆ VIa, IXA RBC, WBC, liver RBC, DNA ؆ Muscle, liver ؆؆ 0 .red blood cell ؍ chorionic villous cells; RBC ؍ white blood cell; CVS ؍ polymorphonuclear neutrophils; WBC ؍ PMN

biochemical diagnosis, it is recommended to analyze biop- -independent enzyme and the glycogen content in the liver.43 sied tissues or gene analysis to secure diagnosis.42 Two genes for the liver and muscle form as well as the respec- tive mutations have been reported.53,54 Phosphorylase Kinase System In conclusion, a major problem in detecting GSD patients is the lack of selective screening methods. We usually have to Defect (GSD VIa, XIII, IX, or X) rely on clinical suspicion and histologic investigation of bi- Phosphorylase kinase (PBK) deficiency is clinically, biochem- opsied tissues. During the last decades, we have tried to de- ically, and genetically manifold. The common liver types are velop methods to screen as well as to establish a reliable divided into several forms, the X-linked liver form (XLG-I diagnostic procedure by analyzing respective enzymes in and XLG-II) and autosomal recessive forms.8,43 For adult- blood cells (Table 7). As shown in Table 7, the homozygosity onset muscular types, the phenotypes of which are very sim- for several GSD types such as type III, IV, and VIa as well as ilar to those of McArdle disease, the existence of several trans- the respective carriers can be detected by simply analyzing mission forms as in the case of liver, namely autosomal blood. For most GSDs, genetic markers have already been recessive and X-linked forms, can be suspected. For severe established (Tables 1 and 2). A further characterization of phenotypes such as neurologic forms42,44 or cardiac forms,45 genotypes can be used for securing the diagnosis sparing the it is not yet clear which kinds of protein kinase are involved in patient a biopsy. An early recognition of patients and distinc- causing the disorders. PBK is the largest and the most com- tion of subtypes help in therapy introduction as well as ge- plex protein kinase and consists of a dimer of octamers with netic counseling. ␣ ␤ ␥ ␦ 4 subunits ( 2 2 2 2)2. Each subunit has tissue-specific characteristics, and furthermore the gene locations of the References 8,43 subunits are also variable (Table 2). The presence of gene- 1. Beaudet AL: Glycogen storage disease, in Wilson JD, Braunwald E, specific isoforms as well as the genetic heterogeneity may Isselbacher KJ (eds): Harrison’s Principles of Internal Medicine. New explain the variability in numerous tissue-related organ-spe- York, NY, Academic Press, 1991, pp 1854-1860 cific clinical pictures of phosphorylase system defects. Even 2. Arion WJ, Lange AJ, Walls HE, et al: Evidence for the participation of for the liver form of the disease, the biochemical diagnosis is independent translocases for phosphate and glucose 6-phosphate in 8,43 the microsomal glucose 6-phosphatase system. J Biol Chem 255: not always possible using blood cells alone. The PBK ac- 10396-10406, 1980 tivity in red cells and leukocytes was low only in the typical 3. Shin YS: Biochemical aspects of glycogen storage disease type I: Sum- X-linked form (XLG I) and an autosomal recessive form.1,8,27,43 mary of the discussions. Eur J Pediatr 152:85-86, 1993 The exact assessment of PBK is indeed difficult because of the 4. Burchell A, Wadell ID, Countaway JL, et al: Identification of the human existence of subunits with different functions and tissue-specific hepatic microsomal glucose 6-phosphatase enzyme. FEBS Lett 242: isozymes. This is further aggravated because the whole system is 153-156, 1988 5. Burlina A, Demirkol M, Muntau M, et al: Increased plasma biotinidase 1,8,27,43 activated by a complex cascade. A few related candidate activity in patients with glycogen storage disease type Ia: Effect of biotin genes are characterized, and several mutations in the respective supplementation. J Inherit Metab Dis 19:209-212, 1996 genes were reported44–52 (Table 1). 6. Lei K, Shelly LL, Pan C, et al: Mutations in the glucose 6-phosphatase gene that cause glycogen storage disease type Ia. Science 262:580-583, 1993 Glycogen Synthase 7. Bashan N, Potashnik R, Peleg E, et al: Uptake and transport of hexoses into polymorphonuclear leukocytes of patients with glycogen storage Deficiency (GSD 0) disease type Ib. J Inherit Metab Dis 13:252-254, 1990 The patients with GSD 0 show similar symptoms of non– 8. Shin YS: Diagnosis of glycogen storage disease. J Inherit Metab Dis 13:419-434, 1990 insulin-dependent diabetes but can accompany symptoms of 9. Gerin I, Veiga-da-Cunha M, Achouri Y, et al: Sequence of a putative hepatomegaly, hypoglycemia, and lactic acidemia. The liver glucose 6-phosphate translocase gene, mutations in GSD type Ib. FEBS form can be diagnosed by measuring the G6P-dependent and Lett 419:235-238, 1997 120 Y.S. Shin

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