Infantile Pompe disease IPD is rapidly progressive; patients with IPD typically present in the first few months of life with severe hypotonia, respiratory distress and hypertrophic cardiomyopathy, among other complications Table 1. Late-onset Pompe disease LOPD is typically slowly progressive primarily involving skeletal muscle without severe cardiomyopathy and encompasses those presenting later than infancy as well as the adult-onset form of the disease.

Enzyme replacement therapy ERT with recombinant human GAA rhGAA, Myozyme and Lumizyme is the only currently approved treatment for Pompe disease The advent of ERT has significantly prolonged survival and improved clinical outcomes in patients with Pompe disease, especially in the infantile form, which was previously known to be fatal by the second year of life when untreated.

Despite treatment with ERT, however, there remains a multitude of persistent complications that significantly limit clinical outcomes. One significant challenge with ERT is the risk of developing antidrug antibodies ADAs to ERT, which have a severe deleterious effect on treatment efficacy and can lead to rapid clinical decline.

Patients with cross-reactive immunological material negative IPD have the highest risk of developing ADAs, as they are completely unable to form endogenous GAA enzyme, resulting in an immunogenic response to the therapeutic protein 13 , Additionally, as patients with IPD are surviving well into adolescence, and patients with LOPD are being identified earlier through diagnostic advancements such as newborn screening 15 , a new natural history is revealing persistent manifestations of the disease despite treatment with ERT 16 , For example, one limitation is the insufficient or lack of glycogen clearance in certain tissue types, such as smooth muscle across vascular, ocular, gastrointestinal and respiratory systems Reports have also revealed white matter lesions in the brain, which was previously thought to remain unaffected in Pompe disease 19 , Although some of these challenges can be resolved to a certain extent through close disease monitoring, adjunctive therapies to ERT and a multi-systemic approach to care, there is a demonstrated need for new therapies that can successfully target these specific manifestations.

Adeno-associated virus AAV vectors will express G6Pase in the liver, improving the abnormalities of GSD Ia. AAV vector administration to young mice accomplished a high level of liver transduction Fig. This phenomenon reflected the episomal nature of AAV vector genomes that are lost as cells divide during growth and development.

Similarly, an rAAV8 vector was administered to a GSD Ia puppy at one day of age and prevented hypoglycemia for 3 h at 1 month of age; however, by 2 months of age the dog became hypoglycemic after 1 h of fasting and retreatment with a new rAAV1 vector was needed to restore efficacy A larger study demonstrated greatly prolonged survival in GSD Ia dogs following treatment with repeated AAV vector administration using a new serotype for each treatment; however, those vectors failed to prevent progression of liver or kidney involvement from GSD Ia 25 , Integrating AAV vectors have been developed for the treatment of GSD Ia The AAV-ZFN vector safely generated DNA breaks in the ROSA26 gene, which allowed integration of the AAV-G6Pase vector by homologous recombination to integrate the G6PC -derived transgene.

Without the ZFN, integration occurs at random breaks in chromosomal DNA at a lower rate Treatment with the peroxisome proliferator-activated receptor PPAR -agonist bezafibrate in GSD Ia mice lowered glycogen and triglycerides in liver Therefore, we tested whether bezafibrate would enhance the efficiency of ZFN-mediated gene editing 27 by normalizing autophagy in the GSD Ia liver Bezafibrate with gene editing decreased liver glycogen and increased G6Pase activity and prevented hypoglycemia during fasting.

Furthermore, bezafibrate-treated mice had a higher number of vector genomes, and ZFN activity was higher. Bezafibrate treatment normalized the impaired molecular signaling in GSD Ia as follows: 1 the expression of PPARα, a master regulator of fatty acid β-oxidation; and 2 the expression of PPARγ, a lipid regulator signaling.

Therefore, bezafibrate improved the hepatic environment and increased the transduction efficiency of AAV vectors in liver, while higher expression of G6Pase corrected molecular signaling in GSD Ia.

Thus, the benefits from stimulating autophagy during gene editing were two-fold: 1 from reversing the hepatosteatosis of GSD Ia 31 , and 2 from increasing AAV vector transduction The prevention of HCA and HCC were described by Lee et al.

The treated mice displayed normal hepatic triglyceride content, had normal blood glucose in response to a glucose tolerance test, had decreased fasting blood insulin levels and maintained normoglycemia over a 24 h fast. A comparison between AAV-PE with another rAAV8 vector containing a minimal G6PC promoter sequence AAV-G6Pase 34 revealed higher transgene expression from the large G6PC promoter sequence in AAV-GPE The high-level G6Pase activity achieved with AAV-GPE might explain the remarkably high efficacy achieved from only few cells expressing G6PC in the liver.

Kim et al. Given the success of gene therapy with AAV-GPE, a Phase I clinical trial is currently underway with that vector NCT GSD Ib is complicated by neutropenia associated with increased risk for infection and related to the deficiency of glucosephosphate transporter G6PT , in addition to the liver and kidney involvement characteristic of GSD I This myeloid dysfunction has resisted AAV vector transduction, which is readily understood related to the episomal status of AAV vector genomes that leads to loss of vector genomes during cell division Consistent with this prediction, AAV vector-mediated gene therapy has reversed hepatic involvement and hypoglycemia when transduction was sufficient.

Neutropenia persisted despite the reversal of biochemical abnormalities in these mice with GSD Ib, which suggested that episomal AAV vector genomes containing G6PT were lost from rapidly dividing neutrophils.

Amalfitano et al. demonstrated that high-level liver expression from a modified adenovirus vector produced circulating GAA in the blood, accompanied by receptor-mediated uptake in the heart and skeletal muscle Although the GAA expression for liver proved to be transient, adenovirus vector-mediated GAA expression from the liver depot achieved high-level biochemical correction throughout the heart and skeletal muscle Adenovirus vector-mediated gene therapy provoked anti-GAA antibodies that interfered with the biochemical correction of muscle However, anti-GAA antibodies could be reduced by including a liver-specific regulatory cassette to drive GAA expression Overall, these studies confirmed high-level production of GAA in the blood corrected the heart and skeletal muscle through cation-independent mannose 6-phoshate receptor CI-MPR mediated uptake of precursor GAA and trafficking to the lysosomes, where GAA was processed and cleared stored glycogen.

More recently AAV vectors have developed to produce secreted proteins including coagulation factors and lysosomal enzymes 45—47 , including GAA in Pompe disease The potential for liver depot gene therapy with AAV vectors to surpass ERT was demonstrated by studies that corrected GAA deficiency Fig.

Importantly, liver depot gene therapy can correct type II myofiber muscles that resist correction from ERT 49 , Later studies suggested the feasibility of clearing sequestered glycogen from the central nervous system CNS following high-level hepatic GAA production 51 , 52 , which can be attributed to CI-MPR-mediated transfer of a lysosomal enzyme such as GAA across the blood—brain barrier One advantage of gene therapy over ERT stems from the continuous, low-level exposure of skeletal muscle to GAA from the liver depot, in contrast to periodic, high-level exposure from ERT The concept of AAV vector-mediated liver-specific transgene expression to suppress antibody responses against therapeutic proteins was developed first in animal models for hemophilia 55 , 56 and later in Fabry disease 47 and Pompe disease 48 , Immune tolerance to GAA was induced by liver-specific expression, which was confirmed by the absence of anti-GAA antibody formation following vector administration 57— Furthermore, low-dose AAV vector administration could induce immune tolerance to GAA that enhanced the efficacy from simultaneous ERT 57 , The induction of immune tolerance to GAA improved the biochemical correction from simultaneous ERT and prevented hypersensitivity reactions by suppressing anti-GAA antibody formation.

The underlying mechanism is the activation of regulatory T cells that suppress antibody responses against GAA latter, which has been termed immunomodulatory gene therapy The high tropism of AAV vectors for the liver reduces the dose requirements for gene therapy in Pompe disease.

Muscle-targeted gene therapy has been attempted by incorporating a highly active muscle-specific regulatory cassette MHCK7 in an AAV vector encoding GAA 62 , but dose requirements were high. Intriguingly, these immune responses against systemic GAA expression with a constitutive promoter can be suppressed by simultaneous administration of an AAV vector containing a liver-specific promoter to induce immune tolerance to GAA 59 , Gene therapy can be enhanced by methods to increase GAA secretion from the liver or to increase CI-MPR expression in skeletal muscle.

The initial study of enhancing secretion of GAA modified the signal peptide of GAA to one from a highly secreted protein to produce a chimeric, secreted GAA 65 , High-level hGAA was sustained in the plasma of mice with Pompe disease for 24 weeks following administration of an rAAV8 vector encoding chimeric GAA; furthermore, GAA activity was increased and glycogen content was significantly reduced in striated muscle and in the brain These data confirmed the feasibility of modifying GAA to drive secretion from transduced hepatocytes, thereby increasing the availability of GAA for the cross-correction of skeletal muscle.

A more recent study of chimeric GAA confirmed the strategy of modifying the signal peptide Another vector containing GAA that combined both modifications of altering the signal peptide and codon-optimization successfully avoided anti-GAA formation at those dosages.

These initial studies suggested that efficacy can be increased from a chimeric, codon-optimized GAA, if immune tolerance to GAA can be achieved. Another strategy to enhance gene therapy in Pompe disease consists of inducing expression of CI-MPR in skeletal muscle 50 , Treatment with the long-acting, selective β2-agonist clenbuterol increased CI-MPR in skeletal muscle and in the brain.

The efficacy of liver depot gene therapy was enhanced by the addition of clenbuterol, as demonstrated by increased rotarod latency, in comparison with vector alone. Glycogen content was lower in skeletal muscles following combination therapy, including the tibialis anterior containing mainly type II myofibers, in comparison with vector treatment alone Consistent with this preclinical data, a Phase I clinical trial revealed improved muscle function and biochemical correction following clenbuterol treatment in addition to ERT, in comparison with ERT alone, for adult patients with Pompe disease Lim et al.

recently reported that an rAAVPHP. The rAAVPHP. B vector containing human GAA under the control of the CB promoter produced widespread GAA at supraphysiologic concentrations in the brain and heart, and glycogen content was significantly decreased in the brain, heart and skeletal muscle following vector administration.

This biochemical correction correlated with the normalization of neuromuscular function. Although the rAAVPHP. B vector would not transduce human tissues and would not be effective in a clinical trial, this proof-of-concept data demonstrated the unprecedented reversal of muscle and nerve involvement with an AAV vector A Phase I clinical trial of liver depot gene therapy for Pompe disease has begun enrolling adult patients NCT This study will evaluate an rAAV8 vector containing a liver-specific promoter to drive wild-type GAA expression.

Rather than frequent infusions of a recombinant protein, as in ERT, gene therapy with an rAAV8 vector will be performed once with long-lasting effects.

Given proof-of-concept studies, it is anticipated that this strategy will induce specific immune tolerance to GAA in Pompe disease with a low dosage of this rAAV8 vector that expresses GAA only in liver, rAAV8 -LSPhGAA 57 , This preclinical data justified a starting dose of 1. The first cohort of patients has been enrolled in this ongoing study.

Recombinant AAV vectors are currently preferred vehicles for the delivery of gene expression cassettes for their favorable safety properties and robust transduction capabilities.

Despite the rapid advances in gene therapy for GSD I and GSD II in the past decades, limited studies have been reported for other GSDs.

Mutations in the AGL gene cause genetic deficiency of GDE, resulting in excessive accumulation of glycogen with short outer branches limit dextrin in multiple tissues, predominantly in liver and muscle.

Progressive hepatic cirrhosis and liver failure can occur with age Table 1 ; hepatic adenomas and hepatocellular carcinoma have been reported in some cases 6 , 70— Muscle weakness is present during childhood, and progressive myopathy and cardiomyopathy are major causes of morbidity in adults 6 , 73— A major hurdle toward developing AAV-mediated gene therapy for GSD III is the inability to package a gene expression cassette containing the large-sized 4.

To overcome this limitation, Vidal et al. The two vectors share an overlap sequence for homologous recombination of the two segments to form the full-length hGDE coding sequence in vivo. Substitution of the hAAT vector with the universal CMV promoter resulted in hGDE expression and glycogen reduction in the heart and skeletal muscles, but not in the liver, likely due to the inactivation of the CMV promoter in the liver.

The use of a liver-active CMV enhancer chicken beta-actin promoter in the dual vectors improved liver correction and rescued muscle function While promising, a major limitation of this approach is that a cell has to acquire both vectors by a high-dose vector administration and then rely on the low-efficiency reconstitution of the full-length hGDE cDNA through homologous recombination, which cannot achieve an efficiency comparable to a single vector system.

In the same article, the authors also reported that administration of an AAV vector expressing a secreted form of human GAA Pompe disease significantly decreased glycogen accumulation in the liver, but this treatment failed to rescue glycemia and muscle function in GSD IIIa mice Recently Pursell et al.

GSD IV is caused by the deficiency of GBE and characterized by the accumulation of a poorly soluble, amylopectin-like glycogen polyglucosan bodies in liver, muscle and the CNS 78— Liver transplantation is the only treatment optional for GSD IV.

Recently Yi et al. reported a gene therapy study in a mouse model of adult form of GSD IV At 3 months of age, GBE enzyme activity was highly elevated in heart, and significantly increased in skeletal muscles and the brain, but not in liver of the AAV-treated mice.

Glycogen contents were reduced to wild-type levels in skeletal muscles and significantly decreased in the liver and brain Plasma biochemistry tests revealed an overall trend of decreased plasma enzyme activities of ALT, AST and CK at 9 months of age, suggesting an alleviation of damage in the liver and muscle from the AAV-GBE treatment However, the same AAV treatment failed to achieve efficacy when mice were treated at an adult age 3 months; unpublished data , which was likely a result of cytotoxic T cell immune responses provoked by the transgene expression human GBE.

Currently, we are evaluating strategies to suppress or evade cellular immune responses during gene therapy in adult mice. GSD V, also known as McArdle disease, is caused by mutations in the PYGM that encodes for the muscle form glycogen phosphorylase myophosphorylase enzyme Table 1.

Patients are frequently detected in the second to third decade of life by exercise intolerance with muscle cramping accompanied by elevated serum creatine kinase 85— There is no effective treatment for this disease, but many patients are able to perform moderate, sustained exercise on a carbohydrate-rich diet with carbohydrate ingestion shortly before exercise 89 , To date, the only gene therapy study for the disease was conducted in an ovine GSD V model Intramuscular injection of a modified adenovirus 5 or an AAV2 vector containing myophosphorylase expression cassettes under the control of a Rous Sarcoma virus or CMV promoter effectively transduced and expressed functional myophosphorylase in the muscle of GSD V sheep, but the activity of myophosphorylase waned over time in all the treated muscles Liver-targeted gene therapy with rAAV8 vectors has efficaciously corrected the glycogen storage of GSD Ia and Pompe disease in preclinical studies Fig.

Proof-of-concept experiments have successfully reversed the effects of GSD in multiple animal models, although further optimization will be required to advance gene therapy to clinical trials for GSDs other than GSD Ia and Pompe disease.

However, successful clinical trials in one or more GSDs will fuel optimism regarding the potential of gene therapy to treat many or all of the GSDs. National Institute of Diabetes and Digestive and Kidney Diseases R01DKA1 to D.

Chen Center for Genetics and Genomics to D. has served on a data and safety monitoring board for Baxter International, and he has received funding from Roivant Rare Diseases.

received an honorarium and grant support in the past from Sanofi Genzyme and Amicus Therapeutics. and Duke University have equity in Asklepios Biopharmaceutical, Inc.

AskBio , which is developing gene therapy for Pompe disease. Additionally, P. and D. have developed technology that is described herein. If the technology is commercially successful in the future, the developers and Duke University may benefit financially.

We would like to acknowledge inspiration and support from Dr Emory and Mrs Mary. Chapman and their son Christopher, and from Dr. John and Mrs. Michelle Kelly. We deeply appreciate the dedication shown by the staff of the Duke Department of Laboratory Animal Resources, as well as undergraduate students at the Duke University.

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Levin , B. and Mortimer , P. eds , GeneReviews®. Seattle, WA , in press. Hepatocellular carcinoma can develop as a long-term complication of liver cirrhosis, rather than transformation of an adenoma to carcinoma, as seen in GSD-I[ , ].

Children with failure to thrive often catch-up in height in adulthood with optimized, individualized dietary management. Muscle symptoms associated with GSD-III can manifest concurrently with liver disease or long after hepatic disorders or even after the resolution of hepatic symptoms during childhood.

Nonetheless, a normal CK level does not entirely exclude the possibility of an underlying muscular disease[ , ].

The median age of onset of CK elevation was reported to be 10 years[ ]. Although muscle involvement becomes clinically more obvious later in life, mild muscle weakness on physical examination, motor developmental delay delayed sitting, delayed standing upright, delayed onset of walking , exercise intolerance, and hypotonia were reported in the majority of pediatric patients with GSD-III[ - ].

Muscle weakness and wasting may slowly progress and become severe by the third or fourth decade of life[ , ].

In a subset of adult patients with GSD-III, muscle symptoms can present in the absence of any clinical or previous evidence of liver dysfunction[ , ]. Muscle weakness, although minimal during childhood, is slowly progressive in nature and may become the predominant feature with significant permanent muscle weakness in adults with type IIIa disease[ ].

Although myopathy generally progresses slowly and is not severely debilitating, some patients may have severe muscle involvement leading to loss of ambulation[ ]. Myopathy can be proximal, distal, or more generalized. Exercise intolerance with muscle fatigue, cramps and pain are evident in more than half of patients[ , , ].

Bulbar or respiratory dysfunctions are rarely seen in GSD-III patients while no clinical involvement of facial or ocular muscles has been described in the literature[ ]. Cardiac involvement in GSD-III is variable.

Cardiac involvement is present in most patients, with varying degrees of severity ranging from ventricular hypertrophy detected on electrocardiography to clinically apparent cardiomegaly[ ].

Mogahed et al [ ] reported that cardiac muscle involvement is less common and mostly subclinical in the pediatric age group. Sudden death has occasionally been reported[ ]. Patients with GSD-III may exhibit facial abnormalities such as indistinct philtral pillars, bow-shaped lips with a thin vermillion border, a depressed nasal bridge and a broad upturned nasal tip, and deep-set eyes, particularly in younger patients[ ].

Some individuals with GSD-III may have an increased risk of developing osteoporosis with reduced bone mineral density which, in part, may be due to suboptimal nutrition, the effects of metabolic abnormalities and muscle weakness[ 41 , , ].

Bone fractures due to osteopenia and osteoporosis were reported in patients with GSD-III[ ]. Polycystic ovary disease has been reported in women with GSD-III with no significant effect on fertility[ ].

Type 2 diabetes may occur during the course of the disease in adulthood[ ]. Michon et al [ ] reported global cognitive impairment in adult GSD-III patients as an underlying cause of psychological and attention deficits seen in this patient group.

Liver histology shows uniform distension of hepatocytes secondary to glycogen accumulation. There is often septal formation, periportal and reticular fibrosis, fine microsteatosis, and less frequently, micronodular cirrhosis without inflammation or interface hepatitis.

Skeletal muscle shows subsarcolemmal glycogen accumulation[ 12 ]. The diagnosis of GSD-III is made by identification of biallelic AGL pathogenic variants on molecular genetic testing. If the diagnosis cannot be established by genetic analysis, demonstrating enzyme deficiency in peripheral leukocytes or erythrocytes, cultured skin fibroblasts or in the liver or muscle tissue samples is necessary.

A practice guideline was published by the American College of Medical Genetics and Genomics in providing recommendations on the diagnosis and management of the complications of GSD-III[ ]. The mainstay of GSD-III treatment is dietary intervention, which aims to maintain normal blood glucose levels while balancing macronutrient and total caloric intake.

This is achieved by the avoidance of fasting, frequent meals enriched in complex carbohydrates and use of UCCS. Continuous enteral feeding may be needed in some cases.

Sucrose, fructose, and lactose are not contraindicated unlike GSD-I. UCCS can be used as early as the first year of life to prevent hypoglycemia. As an alternative, Glycosade ® , an extended-release cornstarch, can also be used[ 87 ].

Caution must be exercised to avoid overtreating with cornstarch or carbohydrates, which may lead to excessive storage of glycogen in the liver and weight gain.

In patients with myopathy, along with managing hypoglycemia, a high-protein diet is recommended as it prevents muscle protein breakdown during glucose deprivation, thereby preserving skeletal and cardiac muscle[ ].

A ketogenic diet alone or in combination with high protein and ketone bodies was also shown to ameliorate cardiomyopathy[ , ]. It has been shown that a high-fat, low-calorie and high-protein diet can reduce cardiomyopathy in individuals with GSD-III[ , ].

The beneficial effects on cardiac or skeletal muscle function of these ketogenic or high-fat diets are possibly related to the increased ketone bodies or fats as fuel sources, or reduced glycogen accumulation through decreased carbohydrate intake. Whether long-term muscular, cardiac, or even liver complications can be prevented by these dietary approaches warrants further studies[ ].

Liver transplantation corrects all liver related biochemical abnormalities but does not correct myopathy or cardiomyopathy[ , , ]. Detailed information about surveillance recommendations on hepatic, metabolic, musculoskeletal, cardiac, nutritional, and endocrine aspects of the disease can be found elsewhere[ ].

Gene therapy and gene-based therapeutic approaches are in development. Branching of the chains is essential to pack a very large number of glycosyl units into a relatively soluble spherical molecule.

Without GBE, abnormal glycogen with fewer branching points and longer outer chains resembling an amylopectin-like structure polyglucosan accumulates in various tissues including hepatocytes and myocytes[ ]. The mapping of the GBE1 gene to chromosome 3p Notably, mutations in the same gene are also responsible for adult polyglucosan body disease.

GSD-IV accounts for only 0. This rare disorder has a prevalence of to [ ]. GSD-IV exhibits significant clinical heterogeneity and phenotypic variability, partly due to variations in tissue involvement, which may be influenced by the presence of tissue-specific isozymes[ , ].

The liver is the primary organ affected, with the classical hepatic form appearing normal at birth but progressing rapidly to cirrhosis in early life, leading to liver failure and death between 3 to 5 years of age[ ].

Besides the complications of progressive cirrhosis including portal hypertension, ascites and esophageal varices, the development of hepatocellular carcinoma was also reported[ ]. In rare cases, the hepatic disease in GSD-IV may not progress or progress slowly[ ].

Patients with the non-progressive hepatic form may present with hepatosplenomegaly and mildly elevated liver transaminases, and experience normal growth. Liver size and transaminase levels may return to normal[ ]. Patients with the non-progressive hepatic form usually survive into adulthood.

GSD-IV can present with multiple system involvement, with the enzyme deficiency in both liver and muscle[ ]. This form of the disease can manifest as peripheral myopathy with or without cardiomyopathy, neuropathy, and liver cirrhosis.

Onset of the disease can be from the neonatal period to adulthood[ ]. The neuromuscular presentation can be divided into four groups based on age at onset[ ].

In the perinatal fetal form, which can lead to hydrops fetalis and polyhydramnios, arthrogryposis develops due to akinesia[ ]. Detection of cervical cystic hygroma during pregnancy may indicate the disease[ ].

Prenatal diagnosis can be performed by determining enzyme activity in cultured amniocytes or chorionic villi samples.

Genetic studies can complement uncertain enzyme activity studies, such as equivocal results in prenatal fetal samples and in patients with higher levels of residual enzyme activity that overlap heterozygote levels[ ]. Mortality is unavoidable in the neonatal period. Liver cirrhosis or liver failure has not been reported.

Severe hypotonia, hyporeflexia, cardiomyopathy, depressed respiration, and neuronal involvement are features of the congenital form of the disease[ , - ].

Liver disease is not severe, and the child dies in early infancy due to other reasons. The childhood neuromuscular form may start at any age with either myopathy or cardiomyopathy[ , ]. Presenting symptoms mainly include exercise intolerance, exertional dyspnea, and congestive heart failure in advanced stages.

The disease can be confined to muscular tissue and serum CK level can be within the normal range. In the adult form, there is isolated myopathy or a multisystemic disease called adult polyglucosan body disease. Onset of symptoms can occur at any age during adulthood, usually after the age of 50, and may exhibit a resemblance to muscular dystrophies.

Symptomatology includes progressive gait difficulty and proximal muscle weakness, which is more pronounced in the arms as compared to the legs. Both upper and lower motor neurons are affected in the disorder.

The disease may manifest as pyramidal tetraparesis, peripheral neuropathy, early onset of neurogenic bladder, extrapyramidal symptoms, seizures, and cognitive dysfunction leading to dementia[ ]. The diagnosis can be established by enzyme activity assay in erythrocytes[ ].

Amylopectin-like inclusions are detected through ultrastructural examination of the central nervous system and skeletal muscle. These inclusions are intensely PAS-positive and diastase-resistant, both in neurons and muscular fibers[ ].

Magnetic resonance imaging shows white matter abnormalities[ ]. Liver biopsy can be diagnostic in patients with hepatic involvement[ ]. The histopathological evaluation of the liver reveals abnormal hepatocellular glycogen deposits in the form of PAS-positive, diastase-resistant inclusions. Ultrastructural examination with electron microscopy reveals accumulation of fibrillar aggregations that are typical of amylopectin.

Typically, enzyme deficiency can be documented through diagnostic assays performed on hepatocytes, leukocytes, erythrocytes, and fibroblasts.

However, patients with cardioskeletal myopathy may exhibit normal leukocyte enzyme activity[ ]. The diagnosis of GSD-IV can be confirmed through histopathological examination, detection of enzyme deficiency, and mutation analysis of the GBE1 gene.

Genetic confirmation is recommended whenever possible in patients with suspected GSD-IV to provide more data for genotype-phenotype correlations in this extremely rare disease. The genotype-phenotype correlation remains unclear for GSD-IV and the same genetic defect may cause different clinical presentations in unrelated patients[ ].

Mutation analysis can also provide crucial diagnostic information in cases with equivocal results of biochemical analyses[ ].

Mutations with significant preservation of enzyme activity may be related with milder e. Hypoglycemia has traditionally been considered a late manifestation and generally develops due to hepatocellular dysfunction caused by progressive cirrhosis. At this stage of the disease, the biochemical profile of the patients is representative of what is observed in other causes of liver cirrhosis.

No specific dietary and pharmacological treatments are available for GSD-IV. There is a lack of established guidelines based on either evidence or expert consensus for the dietary management of GSD-IV. Improvement in clinical, anthropometric, and laboratory parameters was reported with a high-protein and low-carbohydrate diet[ , ].

Derks et al [ ] recently reported improved clinical and biochemical outcomes after dietary interventions including a late evening meal, continuous nocturnal intragastric drip feeding, restriction of mono- and disaccharides, the addition of UCCS, and protein enrichment in patients with GSD-IV.

Individual dietary plans should also aim to avoid hyperglycemia to minimize glycogen accumulation in the liver. At present, there is no effective therapeutic approach other than liver transplantation for GSD-IV patients who are affected by progressive liver disease.

However, anecdotal reports indicate that liver transplantation may not alter the extrahepatic progression of GSD-IV[ ]. The presence of extrahepatic involvement, especially amylopectin storage in the myocardium, may lead to fatal complications following liver transplantation[ - ].

Careful assessment of cardiac function even in the absence of clinical decompensation or consideration of combined liver-heart transplantation is warranted for patients with GSD-IV[ ]. Liver transplantation may provide beneficial effects not only for patients with liver disease but also for those affected by muscular involvement in GSD-IV[ , , ].

This may be explained by systemic microchimerism donor cells presenting in various tissues of the liver recipient after liver allotransplantation and amelioration of pancellular enzyme deficiencies resulting in a decrease in amylopectin in other organ systems[ 12 ].

It has been suggested that the donor cells can transfer enzyme to the native enzyme-deficient cells[ ]. In recent years, animal studies have been conducted to prevent glycogen and polyglucosan body accumulation in GSD-IV patients, and GYS inhibitor guaiacol and DG11 are promising in this regard[ , ].

The molecular target of DG11 is the lysosomal membrane protein lysosome-associated membrane protein 1 LAMP1 , which enhances autolysosomal degradation of glycogen and lysosomal acidification. In the adult polyglucosan body disease mouse model, DG11 reduced polyglucosan and glycogen in brain, liver, heart, and peripheral nerve[ ].

GSD-VI was first reported by Hers[ ] in three patients with hepatomegaly, mild hypoglycemia, an increased glycogen content and deficient activity of glycogen phosphorylase in the liver in GSD-VI is a rare autosomal recessive genetic disease caused by deficiency of hepatic glycogen phosphorylase.

At least three human glycogen phosphorylases exist including muscle, liver, and brain isoforms[ ]. In response to hypoglycemia, liver glycogen phosphorylase catalyzes the cleavage of glucosyl units from glycogen which results in the release of glucosephosphate.

The glucosephosphate is subsequently converted to glucosephosphate. The PYGL gene is currently the only known genetic locus associated with the development of GSD-VI and was mapped to chromosome 14qq22 in [ ].

Incidence of the disease is estimated to be and believed to be underestimated due to nonspecific and variable phenotypes, and a paucity of cases confirmed by genetic testing[ ]. GSD-VI is more prevalent among the Mennonite community, with a prevalence of 1 in , representing the only known population at higher risk for the disease[ ].

GSD-VI is a disorder with broad clinical heterogeneity[ ]. Infants with liver phosphorylase deficiency mainly present with hepatomegaly and growth retardation. The condition typically has a benign course, and symptoms tend to improve as the child grows[ ]. Hepatomegaly usually normalizes by the second decade of life[ ].

The child shows mild to moderate ketotic hypoglycemia related to prolonged fasting, illness, or stressful conditions[ ]. As gluconeogenesis is intact in GSD-VI, hypoglycemia is usually mild.

Despite gross hepatomegaly, the patient may be largely asymptomatic without hypoglycemia. However, there is a range of clinical severity in GSD-VI, with some patients experiencing severe and potentially life-threatening hypoglycemia. There is generally mild ketosis, growth retardation, abdominal distension due to marked hepatomegaly and mildly elevated levels of serum transaminases, triglycerides, and cholesterol.

However, in patients with high residual enzyme activity, biochemical investigations may be normal[ , ]. Hypertriglyceridemia may persist despite treatment[ ].

A few patients showing mild muscular hypotonia, muscle weakness or developmental impairment were observed, but otherwise, no neurological symptoms were reported in the literature[ ]. Sleep difficulties and overnight irritability are common[ ]. In contrast to GSD-I, serum levels of lactic acid and uric acid are generally within the normal range[ 15 ].

However, in a recent clinical study including 56 GSD-VI patients, hyperuricemia was reported as a complication in adolescent and adult patients with GSD-VI, which indicates the need for long-term monitoring of uric acid in older GSD-VI patients[ ].

CK concentration is usually normal. In some patients, severe and recurrent hypoglycemia, pronounced hepatomegaly, and postprandial lactic acidosis have been reported[ ].

Recently, children with GSD-VI have been reported to present with only ketotic hypoglycemia as the sole manifestation of the disease, without the characteristic hepatomegaly[ ]. Mild cardiopathy has also been described for GSD-VI[ ]. The clinical picture of GSD-VI virtually overlaps with phosphorylase kinase PHK deficiency GSD-IX and the differential diagnosis includes other forms of GSDs associated with hepatomegaly and hypoglycemia, especially GSD-I and GSD-III[ ].

It is not possible to distinguish between GSD-VI and GSD-IX based on clinical or laboratory findings alone[ ]. Mutation analysis is the suggested method for the diagnosis of GSD-VI. A liver biopsy is not recommended to establish the diagnosis to avoid an invasive procedure.

Excessive glycogen accumulation with structurally normal glycogen in the liver biopsy is consistent with GSD-VI. Fibrosis, mild steatosis, lobular inflammatory activity and periportal copper binding protein staining have also been reported in GSD-VI patients.

Although it is possible to document glycogen phosphorylase deficiency in frozen liver biopsy tissue or blood cells including leukocytes and erythrocytes, normal in vitro residual enzyme activity may be seen and prevents establishment of a definitive diagnosis by an enzyme assay alone in some patients[ , ].

In GSD-VI, nutrition therapy aims to improve metabolic control and prevent primary manifestations such as hypoglycemia, ketosis, and hepatomegaly, as well as secondary complications including delayed puberty, short stature, and cirrhosis.

The aim of the therapeutic approach is to achieve euglycemia and normoketosis by administration of the appropriate doses of cornstarch.

An extended-release corn starch derived from waxy maize, marketed as Glycosade ® , has been found to have a positive impact in delaying overnight hypoglycemia in children over 5 years of age and adults[ 87 ]. Some individuals with GSD-VI may not require any treatment.

GSD-VI usually has a benign disease course. However, focal nodular hyperplasia, fibrosis, cirrhosis, and a degeneration to hepatocellular carcinoma have been reported in some patients[ - ]. Cirrhosis has been reported in patients as young as preschool age, even within the second year of life[ ].

Based on these findings, aggressive treatment of GSD-VI has recently been suggested to maintain optimal metabolic control and prevent long-term complications[ ]. Long-term monitoring of hepatic function is also recommended[ ]. Glucagon and epinephrine play a critical role in the regulation of glycogenolysis by activation of adenylate cyclase which leads to an increase in the cytosolic concentration of cyclic adenosine monophosphate cAMP.

The increased level of cAMP activates cAMP-dependent protein kinase which activates PHK. PHK is a heterotetramer composed of 4 different subunits α, β, γ, and δ.

Each subunit is encoded by different genes that are located on different chromosomes and differentially expressed in a variety of tissues[ ]. α and β subunits have regulatory functions, the γ subunit contains the catalytic site, and δ is a calmodulin protein[ ].

PHK has a wide tissue distribution with multiple tissue-specific isoforms. The α subunit has two isoforms, a muscle isoform, and a liver isoform, which are encoded by two different genes PHKA1 and PHKA2 , respectively on the X chromosome[ ]. The genetic loci of other subunits are mapped to autosomal chromosomes.

The γ subunit also has muscle and liver isoforms, each of which is encoded by a distinct gene PHKG1 and PHKG2 , respectively. There is only one gene encoding the β-subunit PHKB. However, PHKB is expressed in both muscle and liver[ , ]. Liver PHK deficiency liver GSD-IX can be classified according to the involved gene, the X-linked form GSD-IXa, X-linked glycogenosis and autosomal recessive forms GSD-IXb and GSD-IXc.

GSD-IXa PHKA2 -related GSD-IX is caused by pathogenic variants in the PHKA2 gene on X chromosome. GSD-IXb PHKB -related GSD-IX and GSD-IXc PHKG2 -related GSD-IX are inherited in an autosomal recessive manner and caused by mutations in PHKB and PHKG2 genes, respectively Table 1.

GSD-IXa is further classified into subtypes XLG-I formerly GSD-VIII with no enzyme activity in liver or erythrocytes, and XLG-II with no enzyme activity in liver, but normal activity in erythrocytes[ , ].

GSD-IX is one of the most common forms of GSDs. The frequency of liver PHK deficiency was estimated to be [ 15 ]. On the X chromosome, there are two enzyme loci; one for the alpha subunit of muscle PHK, and one for the alpha subunit of liver PHK. In , the liver PHK gene was located to Xp GSD-IXa is more common in males due to the X-linked inheritance pattern.

Female carriers may become symptomatic due to X chromosome inactivation[ ]. Hepatomegaly, growth retardation, delayed motor development, mild hypotonia, significantly elevated serum transaminase levels, hyperlipidemia, fasting hyperketosis, and hypoglycemia are the main symptoms and findings[ - ].

Rarely described clinical features include splenomegaly, liver cirrhosis, doll-like facies, osteoporosis, neurologic involvement, high serum lactate levels, metabolic acidosis, and renal tubular acidosis[ ].

With increasing age, there is a gradual resolution of both clinical symptoms and laboratory abnormalities. Although puberty may be delayed, eventual attainment of normal height and complete sexual development is still possible[ ].

Most adult patients are asymptomatic[ ]. Unusual presentations including asymptomatic hepatomegaly and isolated ketotic hypoglycemia without hepatomegaly have been reported in affected male children underscoring the importance of screening for GSD-IXa in male patients who are suspected of having GSD with atypical features[ , ].

More severe phenotypes including severe recurrent hypoglycemia and liver cirrhosis have also been reported[ , , ]. Recent findings suggest that GSD-IXa is not a benign condition as is often reported in the literature and patients may have fibrosis even at the time of diagnosis[ ]. GSD-IXc is caused by autosomal recessive mutations in the PHKG2 gene.

The genetic locus of the liver form was located to 16p The presence of PHKG2 mutations has been linked to more severe clinical and biochemical abnormalities, such as an elevated risk for liver fibrosis and cirrhosis[ - ].

Liver cirrhosis can develop in infancy[ ]. Cirrhosis related esophageal varices and splenomegaly, liver adenomas, renal tubulopathy and significant hypocalcemia were other reported clinical findings[ ]. Patients with this condition commonly present with severe hypoglycemia requiring overnight feeding, show very low PHK activity in the liver, and exhibit highly elevated serum transaminase levels.

A wide range of clinical symptoms can be observed, including hypoglycemia during fasting, hepatomegaly, elevated levels of transaminases, hepatic fibrosis, cirrhosis, muscle weakness, hypotonia, delayed motor development, growth retardation, and fatigue[ ].

The genetic cause of GSD-IXb is attributed to mutations in the PHKB gene, which is located on 16qq13 and encodes the beta subunit of PHK[ ]. The main features of the disease include marked hepatomegaly, increased glycogen content in both liver and muscle, and the development of hypoglycemic symptoms after physical activity or several hours of fasting[ ].

Patients with liver fibrosis, adenoma-like mass, mild cardiopathy and interventricular septal hypertrophy were reported[ ]. The muscle symptoms are generally mild or absent, affecting virtually only the liver.

Distinction between GSD-IXb and individuals with pathogenic variants in PHKA2 or PHKG2 cannot be carried out based on clinical findings alone.

Genetic analysis is the preferred first-line diagnostic test in suspected patients. An approach using next-generation sequencing panels is advised due to the involvement of multiple genes.

Liver biopsy can be a valuable diagnostic tool for confirming the diagnosis in cases where there are variants of unknown significance. Histopathological assessment of liver involvement is superior to biochemical parameters[ ].

It is important to keep in mind that PHK enzyme activity can be normal in blood cells and even in liver tissue of affected patients. On the other hand, a reduction in PHK enzyme activity can also occur secondary to other metabolic defects such as pathogenic variants in GLUT2 in Fanconi-Bickel syndrome FBS , PRKAG2 cardiomyopathy syndrome, or mitochondrial complex 1 deficiency[ ].

In patients with GSD-IX, close monitoring of long-term liver and cardiac complications is recommended[ ]. Aggressive structured dietary treatment with UCCS and relatively high protein intake was associated with considerable improvement in growth velocity, energy, biochemical abnormalities, hepatomegaly, and overall well-being of patients with GSD-IX.

Radiographic features of fibrosis were also reported to be improved with early and aggressive dietary management[ ]. General nutritional recommendations for GSD-IX are similar to those for GSD-VI and have recently been published[ ].

The primary defect in FBS is deficiency of glucose transporter 2 GLUT2 , a monosaccharide carrier that is responsible for the transport of both glucose and galactose across the membranes in hepatocytes, pancreatic β-cells, enterocytes, and renal tubular cells. Utilization of both glucose and galactose is impaired in FBS[ ].

Hepatorenal glycogen accumulation and proximal renal tubular dysfunction are the characteristic features of this rare disease[ , ]. FBS follows an autosomal recessive inheritance pattern. The responsible gene, GLUT2 gene solute carrier family 2 member 2, SLC2A2 , was localized to 3q Infants with FBS typically present between the ages of 3 to 10 mo.

In addition to hepatorenal glycogen accumulation and proximal renal tubular dysfunction, FBS is characterized by fasting hypoglycemia, postprandial hyperglycemia and hypergalactosemia, rickets and marked growth retardation.

Patients have entirely normal mental development. In older patients, dwarfism is the most notable finding. Puberty is significantly delayed, with other remarkable observations including a distended abdomen caused by hepatomegaly, deposition of fat on the abdomen and shoulders, and a moon-shaped face[ ].

Some patients may not exhibit hepatomegaly during the early stages of the disease[ , ]. Hyperlipidemia and hypercholesterolemia are prominent and may cause acute pancreatitis. The development of generalized osteopenia occurs early and may result in fractures.

Hypophosphatemic rickets and osteoporosis are characteristics of the disease that emerge later in life[ ]. Tubular nephropathy is characterized by excessive glucosuria, moderate hyperphosphaturia along with persistent hypophosphatemia, hyperuricemia, hyperaminoaciduria, and intermittent albuminuria, collectively referred to as renal Fanconi syndrome[ , ].

Hypercalciuria is also evident. Due to increased renal losses, there is a frequent tendency towards hyponatremia and hypokalemia. Polyuria may develop due to high urinary osmotic load[ ].

Progression to renal failure is not the case. Nephrocalcinosis was also reported in one third of the patients in a recent retrospective study[ ]. There may be mild metabolic hyperchloremic acidosis with normal anion gap due to renal loss of bicarbonate[ ].

Cataracts, a frequently documented consequence of hypergalactosemia, are only present in a small number of patients[ ].

Laboratory findings include fasting hypoglycemia and ketonuria, hyperglycemia and hypergala ctosemia in the postabsorptive state, hypercholesterolemia, hyperlipidemia, moderately elevated alkaline phosphatase, mildly elevated transaminases, normal hepatic synthetic function, hypophosphatemia, hyperaminoaciduria, glucosuria, galactosuria, proteinuria, normal activity of enzymes involved in galactose and glycogen metabolism, normal fructose metabolism, and normal endocrinologic results[ ].

FBS patients develop different patterns of dysglycemia, ranging from fasting hypoglycemia, postprandial hyperglycemia, glucose intolerance, to transient neonatal diabetes to gestational diabetes and frank diabetes mellitus[ ].

The exact molecular mechanisms underlying the occurrence of dysglycemia in individuals with FBS are not yet fully understood. Impaired renal glucose reabsorption, as well as the accumulation of glucose within the hepatocytes, which stimulates glycogen synthesis and inhibits gluconeogenesis and glycogenolysis, result in fasting ketotic hypoglycemia and hepatic glycogen deposition.

Postprandial findings of hyperglycemia and hypergalactosemia are caused by impaired hepatic uptake and diminished insulin response[ ].

Glycated hemoglobin A1c is usually within the normal range due to recurrent hypoglycemia episodes[ ]. Accumulation of glycogen and free glucose in renal tubular cells leads to general impairment in proximal renal tubular function.

Histological evaluation of liver biopsy indicates an excessive buildup of glycogen along with steatosis. Due to the presence of galactose intolerance, newborn screening for galactosemia can sometimes identify patients with FBS[ ].

The diagnosis is ultimately confirmed by genetic analysis of SLC2A2 gene. The management of symptoms involves measures to stabilize glucose homeostasis and compensate for the renal loss of water and various solutes.

Patients typically require replacement of water, electrolytes, and vitamin D, while also restricting galactose intake and adhering to a diabetes mellitus-like diet. Frequent small meals with adequate caloric intake and administration of UCCS are important components of symptomatic treatment.

In cases of renal tubular acidosis, it may be required to administer alkali to maintain acid-base balance. Catch-up growth was reported to be induced by UCCS[ ].

Continuous nocturnal gastric drip feeding may be indicated in some cases with growth failure[ ]. With these measures, the prognosis is good. However, a recent retrospective study reported poor outcome despite adequate metabolic management emphasizing the importance of early genetic diagnosis and facilitating prompt nutritional interventions[ ].

Pompe disease is a typical example of a lysosomal storage disease. The clinical manifestations of Pompe disease are variable, predominantly due to the varying amounts of residual acid alpha-glucosidase GAA activity linked with distinct mutations in the causative gene GAA.

GAA gene is mapped to chromosome 17q Enzyme deficiency results in intra-lysosomal storage of glycogen especially in skeletal and cardiac muscles. There is no genotype-phenotype correlation, but DD genotype in the angiotensin converting enzyme gene and XX genotype in the alpha actinin 3 gene are significantly associated with an earlier age of onset of the disease[ ].

There are mainly two types of GSD-II according to age of onset: Infantile-onset and late-onset Pompe disease. Patients with disease onset before the age of 12 mo without cardiomyopathy and all patients with disease onset after 12 mo of age are included in the late-onset form[ ]. The combined frequency of infantile onset and late onset GSD-II varies between and depending on ethnicity and geographic region.

In the infantile-onset form, cardiomyopathy and muscular hypotonia are the cardinal features and patients die around 1 year of age. Patients also have feeding difficulties, macroglossia, failure to thrive, hearing impairment and respiratory distress due to muscle weakness.

The liver is rarely enlarged unless there is heart failure. Hypoglycemia and acidosis do not occur[ ]. In the late-onset form, involvement of skeletal muscles dominates the clinical picture, and cardiac involvement is generally clinically insignificant depending on the age of onset.

Glycogen accumulation in vascular smooth muscle may cause the formation and subsequent rupture of an aneurysm[ ]. Both severe infantile and asymptomatic adult forms of the disease were observed in two generations of the same family[ ]. Although women with GSD-II do not have an increased risk of pregnancy or delivery complications, pregnancy may worsen muscle weakness and respiratory complications[ ].

As a rule, there is an inverse correlation between the age at disease onset and the severity of clinical manifestations with the level of residual enzyme activity[ ]. Laboratory testing reveals nonspecific elevations in CK, aldolase, aminotransferases, and lactate dehydrogenase.

Elevated urinary tetrasaccharide is highly sensitive but not specific. To establish the final diagnosis, the measurement of enzyme activity in skin fibroblasts or muscle tissue or the demonstration of the responsible mutation is required[ ].

Although it is not curative, ERT has changed the course of Pompe disease since its first use in [ ]. Alglucosidase alfa, a lysosomal glycogen-specific recombinant enzyme, was approved by the European Medicines Agency EMA in in the European Union and by the Food and Drug Administration FDA in in the United States.

pdf ; accessed on November 5, Based on data from later studies, treatment initiation was shifted to the neonatal period.

A new formulation of GAA enzyme, avalglucosidase alfa, improves the delivery of the enzyme to target cells and has 15 times higher cellular uptake when compared with alglucosidase alfa.

The FDA and EMA approved avalglucosidase in and in , respectively, for the treatment of patients who are one year of age and older with late-onset Pompe disease[ ]. Ongoing studies show that avalglucosidase is generally well tolerated in patients with infantile-onset Pompe disease[ ].

Criteria for starting and stopping ERT in adult patients with GSD-II are similar in different countries. While a confirmed diagnosis and being symptomatic are general criteria for starting ERT, patient wish, severe infusion associated reactions, noncompliance with treatment, and lack of effect are criteria for stopping ERT[ ].

Another way to increase the effectiveness of ERT is to use antibodies as an intracellular delivery vehicle. The 3E10 anti-nuclear antibody, that penetrates cells and localizes to the cell nucleus, has been used for this purpose.

VAL is a fusion protein consisting of 3E10 antibody and GAA complex. The presence of 3E10 increases the delivery of GAA to both lysosomal and extra-lysosomal storage of glycogen within cells[ ]. The earlier ERT is started, the better its effectiveness. Therefore, it is recommended that ERT is started before irreversible clinical symptoms begin.

This concept has led to the development of screening programs for Pompe disease[ ]. Recently, it has been shown that in utero alglucosidase alfa treatment, which was started at 24 wk 5 d of gestation and given 6 times at 2-wk intervals through the umbilical vein, was successful[ ].

Although antibodies against the enzyme may develop, a recent study showed that the development of antibodies did not affect the clinical course[ ].

Whether additional treatments such as oral supplementation of L-alanine is beneficial is being investigated[ ]. As an alternative to ERT, studies on gene therapy have also commenced[ ].

Although Danon disease was previously classified as a variant of GSD-II with normal alpha-glucosidase activity, it is still controversial whether it is a real GSD. A lysosomal structural protein, LAMP2, is deficient in Danon disease.

LAMP2 is involved in autophagosome maturation. Disruption of autophagy leads to accumulation of glycogen granules and autophagic vacuoles[ ]. It is an X-linked Xq24 dominant hereditary disease affecting both skeletal and cardiac muscles, and characterized by skeletal and cardiac myopathy, proximal muscle weakness and intellectual disability.

Female patients have a milder disease predominantly involving cardiac muscle[ ]. There is currently no treatment for Danon disease. There are ongoing studies evaluating the efficacy and safety of gene therapy[ ].

Another glycogen storage cardiomyopathy results from PRKAG2 the gene encoding gamma-2 non-catalytic subunit of adenosine monophosphate-activated protein kinase mutations on chromosome 7q The disease is characterized by left ventricular hypertrophy due to altered glycogen metabolism and glycogen storage in cardiac muscle, similar to Danon disease[ - ].

It is inherited in an autosomal dominant pattern. PRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation[ ]. Mutations in the gamma-2 non-catalytic subunit of AMP-activated protein kinase may cause lethal congenital storage disease of the heart, and death in the first year of life[ ].

It is important to differentiate the clinical picture related to PRKAG2 mutations from Danon disease, as management and prognosis are different.

GSD-V is caused by mutations in PYGM gene which is the gene encoding the muscle isoform of glycogen phosphorylase. The PYGM gene is located on 11q The clinical manifestations generally occur during early adulthood with physical activity intolerance and muscle cramps characterized by muscle fatigue and pain, contracture, tachypnea, tachycardia, ptosis, and retinal dystrophy.

Exercise induced rhabdomyolysis can cause transient myoglobinuria, leading to acute renal failure. Hyperuricemia, gout development and thyroid dysfunction are not uncommon[ ]. Many patients are diagnosed with an incidental finding of abnormal serum CK levels[ ]. Echaniz-Laguna et al [ ] studied a family of 13 affected members with adult-onset muscle weakness, and reported a phenotype caused by a dominant myophosphorylase gene mutation p.

The first signs of the disease occurred after 40 years of age with proximal leg weakness, followed by proximal arm weakness. In contrast to McArdle disease, the patients did not have exercise intolerance, second wind phenomenon, markedly increased CK levels, or rhabdomyolysis.

The authors concluded that specific PYGM mutations can cause either dominant or recessive GSDs[ ]. The responsible gene is located on chromosome 12q Exercise induced muscle cramps and myoglobinuria are the main characteristics of GSD-VII.

Neurological examination does not reveal any abnormalities at rest. Muscle weakness and stiffness invariably occur in muscle groups that are subjected to intense or prolonged exertion.

The ischemic exercise test is characterized by the absence of an increase in venous lactate level. Myoglobinuria may develop following exercise.

Nausea and vomiting, icterus, elevated CK, hyperuricemia and reticulosis may also be observed[ ]. In contrast to GSD-V, glucose intake prior to exercise worsens exercise capacity due to blocked use of both muscle glycogen and blood glucose[ ]. The gene is located on chromosome Xq In most patients, clinical findings appear in adulthood and are characterized by muscle weakness and muscle cramps during exercise.

Elevated serum CK level and myopathic findings on electromyography may guide the diagnosis[ ]. The last steps of glycogenolysis are abnormal. The disease is inherited in an autosomal recessive manner and characterized by exercise induced muscle cramps, myalgia, rhabdomyolysis and myoglobinuria.

Serum CK level is increased between episodes[ ]. GSD-XI was first described by Kanno et al [ ] in and characterized by easy fatigue, increase in serum CK, myoglobin, lactate, and pyruvate levels immediately after ischemic work.

The gene locus is on chromosome 11p It is an autosomal recessive disorder, and the gene is located on chromosome 16p GSD-XIII was first described by Comi et al [ ] in in a year-old man with severe deficiency of muscle enolase activity.

The patient had recurrent exercise induced myalgia without cramps. Serum CK concentration was elevated while serum lactate level was normal following ischemic forearm exercise. The related gene is located on chromosome 17p Similar to Danon disease and PRKAG2 variants, glycogenin deficiency may cause left ventricular arrhythmogenic cardiomyopathy.

Patients present with chest pain, progressive weakness, and vague presyncope spells[ ]. There have been significant changes and improvements in the classification, diagnosis, and treatment of GSDs in recent years. We are now more aware that many GSDs, which were previously identified as childhood diseases, may present first in adulthood.

P-Reviewer: El-Shabrawi MH, Egypt; Rathnaswami A, India; Yao G, China S-Editor: Wang JJ L-Editor: Webster JR P-Editor: Zhao S. Home English English 简体中文. Sign In BPG Management System F6Publishing-Submit a Manuscript F6Publishing-世界华人消化杂志在线投稿 RCA Management System. Advanced Search.

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Conflict-of-Interest Statement PDF Copyright Assignment PDF. Citation of this article. Gümüş E, Özen H. Glycogen storage diseases: An update. World J Gastroenterol ; 29 25 : [PMID: DOI: Corresponding Author of This Article.

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ORCID number: Ersin Gümüş ; Hasan Özen Author contributions : Both authors contributed all parts of the study. Conflict-of-interest statement : All the authors report no relevant conflicts of interest for this article. Open-Access : This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.

It is distributed in accordance with the Creative Commons Attribution NonCommercial CC BY-NC 4. Received: December 28, Peer-review started : December 28, First decision : February 1, Revised: February 15, Accepted: April 30, Article in press : April 30, Published online: July 7, Key Words: Glycogen storage disease , Liver , Muscle , Hypoglycemia.

Citation: Gümüş E, Özen H. Open in New Tab Full Size Figure Download Figure. Figure 1 Simplified pathway of glycogen synthesis and degradation in hepatocytes.

Glucose and glycogen convert into one another via synthesis or degradation glycogenolysis through various steps. The liver plays a central role in maintaining normoglycemia. During the fasting state, the liver maintains glucose homeostasis via a metabolic shift from synthesizing glycogen to endogenous glucose production by glycogenolysis and gluconeogenesis.

Specific enzyme or transporter defects in these pathways are associated with clinical and biochemical manifestations including hepatomegaly, hypoglycemia, hyperlipidemia, hypertriglyceridemia, hyperlactatemia, and hyperuricemia.

GSD: Glycogen storage disease; UDP-Glucose: Uridine diphosphate glucose; GlucoseP: Glucose 1-phosphate; GlucoseP: Glucosephosphate; Acetyl-CoA: Acetyl coenzyme A; TCA: Tricarboxylic acid.

Table 1 Overview of glycogen storage diseases. Postprandial hyperglycemia, glycosuria, and hyperlactatemia. Electrocardiographic preexcitation and conduction system disease.

Non-progressive hepatic form. Neuromuscular presentation perinatal, congenital, childhood and adult forms. Myopathy, cardiomyopathy, neuropathy, CNS involvement, APBD.

Severe hepatic involvement reported. Mild hypotonia and cardiopathy reported. Excessive glycogen accumulation with structurally normal glycogen in liver tissue.

Symptomatic female carriers due to X chromosome inactivation. Clinical symptoms and laboratory abnormalities gradually disappear with age. Proximal renal tubular dysfunction. Different patterns of dysglycemia. GSD: Glycogen storage disease; HA: Hepatic adenoma; HCC: Hepatocellular carcinoma; AR: Autosomal recessive; XLR: X-linked recessive; XLD: X-linked dominant; CK: Creatinine kinase; CNS: Central nervous system; APBD: Adult polyglucosan body disease: IBD: Inflammatory bowel disease.

GSD-0; glycogen synthase deficiency. GSD-I; von Gierke disease; hepatorenal glycogenosis. GSD-III; Cori disease; Forbes disease; limit dextrinosis; amylo-1,6-glucosidase deficiency; glycogen debrancher deficiency. GSD-IV; Andersen disease; brancher deficiency; amylopectinosis; glycogen branching enzyme deficiency.

GSD-VI; Hers disease; liver glycogen phosphorylase deficiency. GSD-II; Pompe disease; acid alpha-glucosidase deficiency; acid maltase deficiency; alpha-1,4-glucosidase deficiency.

AMP-activated protein kinase deficiency. GSD-V; McArdle disease; myophospharylase deficiency; muscle glycogen phosphorylase deficiency. GSD-VII; Tarui disease; muscle phosphofructokinase deficiency; GSD of muscle. GSD-IXd; X-linked muscle PHK alpha-1 subunit deficiency.

GSD-X; muscle phosphoglycerate mutase deficiency. GSD-XI; lactate dehydrogenase a deficiency. GSD-XIII; muscle enolase 3 deficiency. GSD-XV; glycogenin deficiency. Provenance and peer review: Unsolicited article; Externally peer reviewed. Ozen H.

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