High Satiety and energy levels levels gycogen lead to the formation of fatty Djagnosis growths disdase xanthomas. Parents may need to alternate nightly duties to avoid sleep deprivation that can lead to lapses. Article PubMed PubMed Central Google Scholar Sims D, Sudbery I, Ilott NE, Heger A, Ponting CP. Ojo AO, Held PJ, Port FK, et al.

Thank you for visiting nature. You are diaease a browser version with limited Satiety and energy levels for CSS. To glgcogen the best glcogen, we recommend you use Proper hydration for athletes more up to diwease browser or turn off compatibility mode in Internet Explorer.

In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Disclaimer: This guideline is glycoge primarily as an educational resource diisease clinicians to lgycogen them provide quality medical sorage.

Adherence diwease this guideline is completely diseaee and does not necessarily Diagnoiss a successful medical outcome. Glycoen guideline should not be diseass inclusive of all proper procedures and tests or oc of other procedures and tests that disaese reasonably directed toward obtaining the Diagnsis results.

In determining the propriety of any specific procedure or test, the clinician should apply his dieease her disase Satiety and energy levels storave to the specific clinical circumstances presented by the individual dlsease or blycogen.

Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not Rejuvenate Your Mind and Body is in dsiease with this guideline.

Clinicians also are Energize your mornings to take notice glyogen the date this guideline was adopted and to consider other medical and scientific information that becomes available after that date.

It also dixease be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other kf. Glycogen storage disease pf I GSD Diagonsis is a rare disease of variable clinical severity that primarily affects gllycogen liver and Optimal nutrition for performance. It is Gymnastics diet essentials for athletes by deficient activity of stotage glucose 6-phosphatase enzyme GSD Ia or a deficiency syorage the microsomal transport proteins for glucose 6-phosphate GSD Ibresulting in excessive accumulation of glycogen and Diabnosis in the liver, kidney, and Diavnosis mucosa.

Patients with GSD Nutritional supplements for athletes have a wide spectrum of clinical vlycogen, including hepatomegaly, hypoglycemia, lactic Diagnnosis, hyperlipidemia, hyperuricemia, and growth retardation.

Individuals with GSD type Ia Freshwater Fish Species have symptoms related to hypoglycemia in infancy when the interval between feedings is Glycgen to 3—4 hours. Diagnosis of glycogen storage disease manifestations of the disease vary in age of onset, gycogen of disease progression, and severity, Satiety and energy levels.

Storagf addition, patients with type Ib have neutropenia, impaired neutrophil dieease, and oc bowel disease. This guideline for Kiwi fruit market analysis management of Healthy vitamin suppliers I was dieease as an Satiety and energy levels resource for health-care providers to facilitate Diabnosis, accurate diagnosis and appropriate management of patients.

A national Electrolyte balance and kidney function of experts Boost energy and vitality various aspects of GSD I met to review the evidence base from the scientific literature and provided their Diangosis opinions.

Consensus was developed in Diagnnosis area of diagnosis, treatment, and management. Conditions to consider Satiety and energy levels the differential diagnosis stemming from presenting features and diagnostic algorithms are discussed.

Aspects of glycoen evaluation and nutritional disrase medical management, including Youthful appearance secrets coordination, genetic counseling, hepatic and renal transplantation, and prenatal diagnosis, are also addressed.

A guideline that facilitates accurate diagnosis and optimal management of patients with GSD I was developed. Diaease guideline helps health-care providers recognize patients with all forms of GSD I, expedite diagnosis, and minimize adverse sequelae oof delayed diagnosis and inappropriate management.

Atorage also helps to identify gaps in scientific knowledge that exist today and suggests future studies. Murielle M. Véniant, Shu-Chen Lu, … Jennifer L. Eka Melson, Uzma Vlycogen, … Melanie J.

This guideline is intended Diagnosis of glycogen storage disease an educational resource. It highlights current practices and therapeutic Fiber internet connection to the diagnosis diseasee management of GSD Diagnosie and its early and gltcogen complications.

Invon Gierke described Antioxidant supplements for athletic performance storage disease type I GSD I Diagnoais reviewing the autopsy reports of Fat loss aid children whose livers and diseade contained Green tea weight loss amounts of glycogen.

Two patients had almost total deficiency of hepatic G6Pase; the remaining four patients had Diagnosis of glycogen storage disease enzyme activity. Early on, vlycogen authors recognized the variability of the hepatic GSDs.

InNarisawa et al. Deficiency of glcyogen enzyme Eating disorder triggers results in Storge Ia, and deficiency of G6PT results od GSD Ib.

The human G6Pase stoage, G6PCis a single-copy gene OMIM located on chromosome 17q21, which was cloned in by Lei et al. The human G6PT gene, SLC37A4 OMIMwhich causes GSD Ib, was cloned and found to be located on chromosome 11q SLC37A4 spans ~ 5. G6Pase is a multipart enzyme system located in the endoplasmic reticulum membrane.

It is a key enzyme in regulation of blood glucose BG levels. Deficiency of glucose 6-phosphatase activity or its microsomal transport proteins results in excessive accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa. Clinical characteristics include doll-like facies, poor growth, short stature, and a distended abdomen due to pronounced hepatomegaly and nephromegaly.

Biochemical manifestations include hypoglycemia, hyperlipidemia, hypertriglyceridemia, hyperlactatemia, and hyperuricemia. Patients with type Ib also have neutropenia and impaired neutrophil function, resulting in recurrent bacterial infections and oral and intestinal mucosa ulceration.

Neutropenia may also be observed in a subset of GSD Ia patients. GSD I is an autosomal recessive, pan-ethnic disorder with genetic mutations identified in Caucasians, Ashkenazi Jews, Hispanics, and Asians. There are many known pathogenic mutations in both G6PC and SLC37A4 genes.

Symptoms of hypoglycemia typically appear only when the interval between feedings increases, such as when the infant starts to sleep through the night or when an intercurrent illness disrupts normal patterns of feeding. Very rarely, hypoglycemia may be mild, causing a delay in the diagnosis until adulthood when liver adenomas and hyperuricemia are detected.

Patients may present with hyperpnea due to lactic acidosis, which may simulate that occurring in pneumonia. The condition may not be recognized until the infant is several months old with an enlarged liver and protuberant abdomen noted on a routine physical examination.

Ultrasound imaging of the liver is similar in GSD I, GSD III, and several other liver storage disorders. However, the presence of nephromegaly and the characteristic biochemical abnormalities seen in GSD I provide clues to the diagnosis.

Untreated patients typically appear short for age, with a round face and full cheeks, giving them a cushingoid appearance. They have failure to thrive and delayed motor development.

Cognitive development is usually normal unless the patient has cerebral damage from recurrent hypoglycemic episodes. Longer intervals between feedings cause more severe hypoglycemia accompanied by lactic acidemia and metabolic acidosis.

Long-term complications are common and are beginning to be more recognized and understood. In most individuals with GSD I, hepatomegaly decreases with age; however, development of liver adenomas is common with increasing age, and some individuals develop hepatocellular carcinoma HCC.

Polycystic ovaries have been documented in females with GSD I after 4 years of age, but fertility is not thought to be reduced.

Early atherosclerosis with risk for ischemic stroke is a potential long-term concern. The circulating concentration of free fatty acids is markedly increased, whereas blood β-hydroxybutyrate levels are only mildly or moderately increased relative to the corresponding free fatty acid levels.

Eruptive xanthomata may appear on the extensor surfaces of the extremities and on the buttocks. The platelet defects are secondary to the systemic metabolic abnormalities and may be corrected by improving control of the metabolic state.

Although hypoglycemia becomes less severe with increasing age, inadequate therapy causes pronounced impairment of physical growth, delayed onset of puberty, and many long-term sequelae of the disease.

However, normal growth can occur, provided that patients maintain good metabolic control at an early age. A majority of patients with GSD I have nephromegaly that is readily demonstrable by ultrasonography. The proximal tubular dysfunction is reversible with improved metabolic control of the disease.

Severe renal injury with proteinuria, hypertension, and decreased creatinine clearance due to focal segmental glomerulosclerosis and interstitial fibrosis, ultimately leading to end-stage renal disease, may also be seen in young adults. Patients with GSD Ib have similar clinical and biochemical abnormalities in addition to neutropenia persistent or cyclic —the severity of which varies from mild to complete agranulocytosis—associated with recurrent bacterial infections.

They frequently develop inflammatory bowel disease Crohn disease—like enterocolitis and may have an increased prevalence of thyroid autoimmunity and hypothyroidism. After a meeting during which published material and personal experience were reviewed by the panel, experts in the various areas reviewed the literature in these areas and drafted the guidelines.

The participants provided conflict of interest statements and their conflicts are stated in the Acknowledgments section. All members of the panel reviewed and approved the final guidelines. Consensus was defined as agreement among all members of the panel. For the most part, the evidence and resulting recommendations are considered expert opinion because additional levels of evidence were not available in the literature.

Penultimate drafts of these guidelines were shared with an external review group consisting of Yuan-Tsong Chen, Philippe Labrune, Areeg El-Gharbawy, and Kathy Ross. The working group considered their suggestions and changes were made as considered appropriate.

This guideline is directed at a wide range of care providers. The diagnosis in a classic case of GSD I is usually straightforward.

The principal differential diagnosis includes other forms of GSD associated with hepatomegaly and hypoglycemia, especially GSD type III and Fanconi—Bickel syndrome, a glucose transporter 2 transporter defect classified as GSD XI, which is not involved in the glycogen metabolism pathway Table 1and, possibly, GSD VI and IX.

GSD I and III have several features in common, including hepatomegaly, hypoglycemia, and hyperlipidemia. However, some key differences between GSD I and GSD III help to differentiate these two disorders.

Patients with GSD I typically present earlier in the first few months of life with severe fasting hypoglycemia within 3—4 hours after feeding. Hypoglycemia is usually not as severe in patients with GSD III because gluconeogenesis is intact and the peripheral branches of the glycogen molecule can be mobilized by the action of hepatic phosphorylase.

Nonetheless, for reasons that are not well understood, some patients with GSD III have an early clinical onset and experience severe hypoglycemia after a brief period without feeding.

Blood β-hydroxybutyrate levels increase only modestly in GSD I, 5354 in contrast to marked hyperketonemia with fasting hypoglycemia characteristic of GSD 0, III, VI, and IX.

At the time of diagnosis, serum concentration of hepatic transaminase aspartate aminotransferase and alanine aminotransferase are increased in GSD I and often return to normal or near-normal levels with appropriate treatment.

By contrast, serum aspartate aminotransferase and alanine aminotransferase levels are typically higher in GSD III, VI, and IX, and increased levels tend to persist despite treatment.

Although elevated transaminase levels and hepatomegaly are common to many primary liver diseases and other metabolic disorders, hypoglycemia is distinctly uncommon until the development of end-stage liver disease for most disorders, except GSDs 6768 and disorders of fructose metabolism.

An increase in creatine phosphokinase is also often noted in GSD IIIa due to involvement of skeletal and cardiac muscle; however, a normal creatine phosphokinase concentration does not rule out muscle involvement.

Whereas patients with GSD VI and GSD IX are usually reported to be relatively mildly affected, some patients are more severely affected and closely resemble patients with GSD III. Hypoglycemia and ketosis are not typical features of GSD IV. In this disorder, liver dysfunction that progresses to liver cirrhosis is a typical clinical feature.

Hypoglycemia is a late finding and is typically only observed in the setting of liver failure. In GSD IV, abnormally structured glycogen resembling plant-like fibers amylopectin accumulates in the liver.

Fructose-1,6-bisphosphatase deficiency, 697071 a disorder of gluconeogenesis, and Fanconi—Bickel syndrome GSD XI 72737475 both have some features that may be confused with GSD I Table 1. Because of severe hepatomegaly, lysosomal storage disorders such as Gaucher disease and Niemann—Pick type B disease may initially be confused with GSD I.

In both these storage diseases, however, there is striking splenomegaly, which is an important distinguishing feature, and hypoglycemia does not occur.

: Diagnosis of glycogen storage disease

Glycogen Storage Diseases - Children's Health Issues - MSD Manual Consumer Version	Tools Tools. What links here Related changes Upload file Special pages Permanent link Page information Cite this page Get shortened URL Download QR code Wikidata item. Download as PDF Printable version. In other projects. Wikimedia Commons. Medical condition. Journal of Neonatal-Perinatal Medicine. doi : PMID S2CID Veterinary Pathology. New England Journal of Medicine. ISSN Retrieved 5 July Cleveland Clinic. Retrieved MedLine Plus. Association for Glycogen Storage Diseases AGSD. October Archived from the original on 11 April Vazquez Cantu, D. Ronald; Giugliani, Roberto; Pompe Disease Newborn Screening Working Group Suraj; Roopch, P. Sreedharan; Kabeer, K. Abdulkhayar; Shaji, C. Velayudhan July Archives of Medicine and Health Sciences. OMIM — Online Medelian Inheritance in Man. Peter A. July Genetics in Medicine. Medscape Reference. Retrieved October 24, Myogenic hyperuricemia. A common pathophysiologic feature of glycogenosis types III, V, and VII. N Engl J Med. doi: McArdle Disease. Treasure Island, Florida FL : StatPearls Publishing. Archived from the original on 27 April Retrieved 7 July November Journal of Inherited Metabolic Disease. eMedicine Medscape Reference. Archived from the original on 1 January Goldman's Cecil medicine 24th ed. ISBN Genetics Home Reference. PMC Molecular Genetics and Metabolism. Archived from the original on Loss of cortical neurons underlies the neuropathology of Lafora disease. Polyglucosan storage myopathies. Mol Aspects Med. Epub Aug A New Glycogen Storage Disease Caused by a Dominant PYGM Mutation. Ann Neurol. Epub Jun 3. Neuromuscular Disorders. A case of myopathy associated with a dystrophin gene deletion and abnormal glycogen storage. Muscle Nerve. February Pediatric Neurology. Acta Myologica. Annals of Indian Academy of Neurology. Practical Neurology. Retrieved May 24, MedLink Neurology. Biochemical Journal. April Clinical Physiology. Journal of Thyroid Research. Living With McArdle Disease PDF. IamGSD Internation Association for Muscle Glycogen Storage Disease. Orphanet Journal of Rare Diseases. Molecular Genetics and Metabolism Reports. Frontiers in Neurology. North American Journal of Medical Sciences. Frontiers in Physiology. ISSN X. June Endocrinologia Japonica. Journal of Cachexia, Sarcopenia and Muscle. Journal of Pediatric Neurosciences. Journal of the Neurological Sciences. Brain: A Journal of Neurology. Human Mutation. NORD National Organization for Rare Disorders. Retrieved 23 March British Journal of Sports Medicine. Journal of Inborn Errors of Metabolism and Screening. Classification D. ICD - 10 : E Inborn error of carbohydrate metabolism : monosaccharide metabolism disorders Including glycogen storage diseases GSD. Congenital alactasia Sucrose intolerance. Glucose-galactose malabsorption Inborn errors of renal tubular transport Renal glycosuria Fructose malabsorption De Vivo Disease GLUT1 deficiency Fanconi-Bickel syndrome GLUT2 deficiency. Essential fructosuria Fructose intolerance. GSD type 0 glycogen synthase deficiency GSD type IV Andersen's disease, branching enzyme deficiency Adult polyglucosan body disease APBD Lafora disease GSD type XV glycogenin deficiency. GSD type III Cori's disease, debranching enzyme deficiency GSD type VI Hers' disease, liver glycogen phosphorylase deficiency GSD type V McArdle's disease, myophosphorylase deficiency GSD type IX phosphorylase kinase deficiency Phosphoglucomutase deficiency PGM1-CDG, CDG1T, formerly GSD-XIV. Glycogen storage disease type II Pompe's disease, glucosidase deficiency, formerly GSD-IIa Danon disease LAMP2 deficiency, formerly GSD-IIb. Pyruvate carboxylase deficiency Fructose bisphosphatase deficiency GSD type I von Gierke's disease, glucose 6-phosphatase deficiency. Glucosephosphate dehydrogenase deficiency Transaldolase deficiency SDDHD Transketolase deficiency 6-phosphogluconate dehydrogenase deficiency. Hyperoxaluria Primary hyperoxaluria Pentosuria Fatal congenital nonlysosomal cardiac glycogenosis AMP-activated protein kinase deficiency, PRKAG2. Authority control databases : National Japan. Diseases of muscle , neuromuscular junction , and neuromuscular disease. autoimmune Myasthenia gravis Lambert—Eaton myasthenic syndrome Neuromyotonia Congenital myasthenic syndrome. Limb-girdle muscular dystrophy 1 Oculopharyngeal Facioscapulohumeral Myotonic Distal most. Calpainopathy Limb-girdle muscular dystrophy 2 Congenital Fukuyama Ullrich Walker—Warburg. dystrophin Becker's Duchenne Emery—Dreifuss. collagen disease Bethlem myopathy PTP disease X-linked MTM adaptor protein disease BIN1-linked centronuclear myopathy cytoskeleton disease Nemaline myopathy Zaspopathy. Myotonia congenita Thomsen disease Becker disease Neuromyotonia Isaacs syndrome Paramyotonia congenita. Hypokalemic Thyrotoxic Hyperkalemic. Central core disease. Brody disease ATP2A1. Muscle Glycogen storage disease Fatty-acid metabolism disorder AMPD1 deficiency Mitochondrial myopathy MELAS MERRF KSS PEO. Glycogen is synthesized in the cytosol of liver parenchymal cells in an ATP-dependent process. Glucose freely enters the liver and is rapidly phosphorylated to glucosephosphate by glucokinase. Glucosephosphate is then converted to glucosephosphate via the enzyme phosphoglucomutase. Glucosephosphate serves as the starting point for glycogen synthesis. In the presence of uridine triphosphate UTP , UDP-glucose pyrophosphorylase converts glucosephosphate to UDP-glucose. The glucose portion of UDP-glucose can then be added to existing glycogen, or can be added to the protein glycogenin to create a new glycogen molecule. Glycogen synthase catalyzes the formation of α -1,4-linkages necessary for elongating glucose chains. With the formation of many long chains and branch points, a tree-like glycogen molecule is created; the numerous branches allow for the addition or removal of multiple glucose molecules at once as needed by the body. In the early stages of fasting, the liver provides a steady source of glucose from glycogen breakdown. Glycogen phosphorylase is activated via phosphorylation by phosphorylase b kinase. Glycogen phosphorylase cleaves the α -1,4-glycosidic bonds, releasing glucose 1-phosphate. A second enzyme, debrancher enzyme, is required for removal of branch point glucose residues attached via α -1,6-linkage. Glucosephosphate is subsequently converted by phosphoglucomutase to glucosephosphate, and glucose 6-phosphatase catalyzes the last step of glycogenolysis; it hydrolyzes the phosphate group from glucosephosphate to create free glucose that can be released from the liver into the systemic circulation. Of note, glucosephosphatase is not present in the muscles so the muscle only forms of GSD are not associated with hypoglycemia. Normally, only with prolonged fasting is glucose generated in the liver from noncarbohydrate precursors through gluconeogenesis, but this can be an important source of endogenous glucose production in the ketotic forms of GSD. Glycogen storage disease type I, also known as von Gierke disease, is an inborn error of metabolism due to deficiency of the glucosephosphatase complex. This multi-component complex, referred to at the G6Pase system, or G6Pase- α , was hypothesized by Arion et al. to consist of four separate proteins, including the G6Pase- α catalytic subunit G6PC , the glucosephosphate transporter G6PT , an inorganic phosphate transporter, and a glucose transporter [ 3 ]. There are at least two known forms of GSD type I: GSD Types Ia and Ib; these are due to defects in the G6PC and G6PT, respectively. The existence of a third and fourth type, GSD Types Ic and Id, have been largely debated since they do not differ from GSD Type Ib clinically, enzymatically, or genetically [ 4—6 ]. GSD Ia OMIM was the first inborn error of metabolism proven to be caused by an enzyme deficiency. In , Gerty and Carl Cori demonstrated deficiency of glucosephosphatase activity in liver homogenate from five patients with a clinical diagnosis of von Gierke disease [ 7, 8 ]. In two of these cases, which were fatal, there was virtual absence of enzyme activity. The glucosephosphatase- α catalytic subunit is expressed in the liver, kidneys, and intestinal mucosa. It is the key enzyme in homeostatic regulation of blood glucose levels, and GSD type Ia has the distinction of being the only glycogen storage disease to be both a disorder of glycogenolysis and gluconeogenesis. Affected individuals usually present in the first year of life with severe fasting hypoglycemia, hepatomegaly, failure to thrive, growth retardation, and developmental delay. Other common findings related to hypoglycemia include sweating, irritability, muscle weakness, drowsiness, and seizures. Symptoms usually become apparent as infants are weaned from frequent feeds. In addition to severe fasting hypoglycemia, biochemical studies reveal hyperlactatemia, hyperuricemia, and hypertriglyceridemia. Children often experience bruising and epistaxis due to impaired platelet function, and normochromic anemia may be present. Children with GSD type Ia develop a markedly protuberant abdomen due to massive stores of liver glycogen. The spleen, however, remains normal in size and cirrhosis does not develop. Other physical findings include truncal obesity, doll-like facies, short stature, and hypotrophic muscles. With optimal metabolic control, the hepatomegaly improves and growth normalizes. Complications including hepatic adenomas, osteoporosis, focal segmental glomerulosclerosis, and a small fiber neuropathy used to be common in the 2nd and 3rd decades of life, but the frequency of these complications has markedly decreased with improvements in therapy and good metabolic control [ 9, 10 ]. Management of hepatic adenomas when they occur remains a source of debate. Most adenomas appear during puberty, and they stabilize following adolescence if metabolic control is optimized. Recently, regression of hepatic adenomas has been reported with improvement in patients whose metabolic control improved [ 11 ]. Since hepatocellular carcinoma in GSD Ia arises from adenomas, frequent imaging of adenomas with MRI and ultrasounds is commonly used. Since glucosephosphatase is also in the kidneys, renal complications can also occur. Decreased glomerular filtration rate is due to focal segmental glomerulosclerosis and interstitial fibrosis. Dysfunction of the proximal tubules leads to Type II renal tubular acidosis, and distal tubular dysfunction is associated with hypercalciuria. Furthermore, metabolically compensated patients show hypocitraturia that worsens with age [ 12 ]. Treatment with ACE inhibitors can slow the progression of kidney damage, and improved metabolic control may slow or even reverse renal disease. Unlike other complications in GSD Ia, kidney stone formation is not primarily related to metabolic control. Hypocitraturia develops in most people with GSD Ia during adolescence, and citrate supplementation has been successful at preventing renal calcification. Patients with large hepatic adenomas may have severe, iron refractory anemia. This anemia has been observed to resolve spontaneously after adenoma resection or liver transplantation. Based upon these findings, it was determined that large adenomas may express inappropriately high levels of hepcidin mRNA [ 13 ]. Hepcidin is a peptide hormone that has been implicated as the key regulator of iron by controlling iron absorption across the enterocyte and macrophage recycling of iron. The increased hepcidin expression in the GSD adenomas is thought to interrupt iron availability and cause iron restricted anemia. GSD Type Ia has a disease incidence of approximately 1 in , births and a carrier rate of approximately 1 in The disorder is found in ethnic groups from all over the world, and the disease is more common in people of Ashkenazi Jewish, Mormon, Mexican, and Chinese heritage [ 14—16 ]. The disorder is associated with mutations in the G6PC gene on chromosome 17q21 which encodes the glucosephosphatase- α catalytic subunit. GSD Ia has classic autosomal recessiveinheritance. G6PC spans While liver biopsies are no longer required for diagnosing this condition, glycogen filled hepatocytes with prominent steatosis are seen in GSD type Ia. Unlike other forms of GSD, however, fibrosis and cirrhosis do not occur. Hepatocellular carcinoma appears to arise from inflammatory adenomas, and chromosomal alterations have been described in the cancerous lesions with proto-oncogene activation leading to dysregulation of insulin-glucagon-growth hormone signaling [ 22 ]. In patients with von Gierke disease, the inability to convert glucosephosphate to glucose results in shunting of G6P to the pentose phosphate shunt and the glycolytic pathway. This, in turn, results in increased synthesis of uric acid, fatty acids and triglycerides. Dietary treatment has immensely improved prognosis. The aim of treatment is to prevent hypoglycemia and counter-regulation thereby minimizing the secondary metabolic derangements. Cornstarch feeds can be spaced usually to every hours in older children and adults. Adding glucose is not recommended since it stimulates insulin production and offsets the advantage of the starch. Of note, a new extended release formulation Glycosade was recently introduced for night feeds, and it has allowed older children and adults to have a 7—10 hour period of coverage without sacrificing metabolic control [ 25 ]. Intake of galactose, sucrose, and fructose is restricted since these sugars will worsen the hepatomegaly and metabolic derangements. The GSD diet is very prohibitive, and it can be difficult for individuals to get all required nutrients without multivitamin supplementation. Other medications are also commonly used to prevent complications. Allopurinol is prescribed when serum urate concentrations are elevated, and fish oil supplementation or a prescription fibrate may be used to lower triglycerides and reduce the risk of pancreatitis. Treatment with an angiotensin-converting enzyme ACE inhibitor is used in patients with proteinuria to reduce intraglomerular capillary pressure and provide renoprotection. Preventive calcium and vitamin D 3 supplementation is also recommended to prevent osteoporosis. Most patients with GSD Ia are clinically doing well into adulthood, and complications are becoming uncommon as metabolic control has improved. Many successful pregnancies have occurred [ 26 ]. At times, intravenous glucose support may be required. Surgery should be undertaken with caution due to a bleeding tendency and risk of intraoperative lactic acidosis. Orthotopic liver transplantation has been performed for some individuals with unresectable adenomas or hepatocellular carcinoma. Liver transplantation, however, is deemed a treatment of last resort since renal failure has been a common complication due to the impact of immunosuppression on abnormal kidneys [ 27 ]. Early in life, patients with GSD Ib may be clinically and metabolically identical to those with GSD Ia. With aging, however, most patients develop neutropenia and inflammatory bowel disease. The neutropenia is the hallmark feature of GSD Ib, but the age of onset and clinical course are variable. It may be present at birth or not appear until late in childhood as cyclic or permanent neutropenia. This nearly universal complication usually appears between 5—12 years of age, but cases as young as 13 months have been reported. Unlike inflammatory bowel disease in the general population, GSD enterocolitis is most commonly located in the small intestine [ 28 ]. Diarrhea and abdominal pain may be late manifestations of the co-morbidity, and it often presents as growth failure, severe anemia, or perioral infections. A normal colonoscopy does not rule out the condition, and a capsule endoscopy sometimes is required to establish its presence. While rare in the general population 1 in 1,, individuals , high risk populations include people of Native American, Iranian Jewish, and Italian heritage. The SLC37A4 gene is located on 11q The histologic appearance of a GSD Ib liver is identical to that of GSD Ia. Establishing the diagnosis of GSD Ib is therefore a challenge since enzymatic testing cannot be relied upon. While almost all glycogenolytic enzymes are found in the cytoplasm, glucosephosphatase is localized to the inner luminal wall of the endoplasmic reticulum. This means that glucosephosphate must cross the membrane of the endoplasmic reticulum in order to act as substrate for glucosephosphatase. This transport protein for glucosephosphate is defective in GSD Ib. Measurement of glucosephosphate translocase activity is difficult to measure, however, and requires fresh unfrozen liver tissue. While liver sample with intact hepatocytes and microsomes will show deficient glucosephosphatase activity because the translocase cannot deliver the G6P substrate to the ER lumen, microsomes disrupted by solubilization or damage from freezing will show normal glucosephosphatase enzyme activity because the substrate is now readily accessible. Due to the difficulty of the biochemical assay, most clinical diagnostic laboratories do not offer such testing and diagnosis by molecular genetic testing is recommended [ 21 ]. Treatment guidelines for patients with GSD Ib are similar to those for GSD Ia with the addition of therapy for the neutropenia and GSD enterocolitis. Recombinant human granulocyte-colony-stimulating factor GCSF , a cytokine that induces proliferation and differentiation of bone marrow precursor cells into mature neutrophils, should be used to treat neutropenia if infections, severe mouth ulcers, or chronic diarrhea are occurring. The GSD Ib population has been prone to untoward effects massive splenomegaly, splenic sequestration, splenic rupture, and portal hypertension with GCSF therapy. Therefore, a starting dose of 2. Supplementation with high dose vitamin E appears to boost the neutrophil count and improve function in GSD Ib, and supplementation may allow lower GCSF doses to be used [ 34 ]. Non-absorbable salicylates Pentasa, Asacol, and Lialda are the first line therapies for GSD enterocolitis. Steroids and immunomodulators must be used with caution due to the metabolic consequences and associated immune dysfunction [ 34 ]. Glycogen storage disease type II acid maltase deficiency, or Pompe disease OMIM is caused by a deficiency of α -1,4 glucosidase, an enzyme required for the degradation of lysosomal glycogen [ 35 ]. The disorder was initially described by Johannes Pompe in [ 36 ]. It is the only form of GSD to be classified as a lysosomal storage disorder. Pompe disease is purely a neuromuscular form of GSD which does not present with metabolic abnormalities because the lysosomal enzyme defect lies outside of intermediary metabolism. Instead, storage of glycogen occurs mainly in skeletal muscle and leads to loss of muscle function. Pompe disease has a broad clinical spectrum with variable age of onset, severity of symptoms, and rate of disease progression. The disorder encompasses a continuum of phenotypes ranging from a rapidly progressive infantile form to a slowly progressive late-onset form. In general, however, Pompe disease is classified into three different subtypes, including infantile, juvenile, and adult forms. There is clinical correlation with the amount of α -1,4-glucosidase expression: residual enzyme activity is found in the adult form, while enzyme activity is completely absent in the severe infantile form. It is important to note that mental development and blood glucose concentrations are normal in all forms of Pompe disease. The classic infantile form is the most severe. Affected infants present shortly after birth with profound hypotonia, muscle weakness, and hyporeflexia. An enlarged tongue and hypertrophic cardiomyopathy are characteristic. Diagnosis may be based on typical EKG findings which include large QRS complexes and shortened PR intervals [ 37 ]. The liver is normal in size. Sensorineural hearing loss is also prevalent and a less recognized feature [ 38, 39 ]. Without therapy, the disease is rapidly fatal with children usually dying of cardiopulmonary failure or aspiration pneumonia by two years of age. In the juvenile form of the disease, affected children have hypotonia and weakness of limb girdle and truncal muscles. Motor milestones are delayed, and the myopathy is more gradual in nature. There is no overt cardiac disease, and the patient usually dies from respiratory failure before adulthood without therapy. The vast majority of patients with Pompe disease are adults. Adult-onset Pompe disease has a long latency and affected individuals may live to old age. Decreased muscle strength and weakness develop in the third or fourth decade, but cardiac involvement, if any, is minimal. Glycogen accumulates in vascular smooth muscle cells and there are rare reports of death from ruptured aneurysms [ 40, 41 ]. Slow, progressive weakness of the pelvic girdle, paraspinal muscles, and diaphragm leads to loss of mobility and respiratory function. Respiratory muscle weakness is the leading cause of death. The incidence of Pompe disease is estimated to be approximately 1 in 40, to 1 in 50, The disorder can be found in ethnically diverse populations, including European Caucasians, Hispanics, and Asians, and several mutations are more common in some populations due to founder effects. For more information, the reader is referred to the Pompe Disease Mutation Database at www. α -1,4-glucosidase is encoded by the GAA gene located on the long arm of chromosome 17 at 17q The gene is composed of 20 exons and over different mutations have been reported [ 19 ]. Of note, while most mutations will be picked up by gene sequencing, at least 11 different gross deletions and one gross insertion have been reported which would not be detectable using this method [ 19 ]. Prenatal diagnosis is possible via enzyme assay or DNA analysis of chorionic villi obtained between 10—12 weeks gestation. There appears to be genotype-phenotype correlation, with specific mutations associated with infantile, juvenile, and adult-onset disease [ 46—48 ]. Severe mutations which lead to complete loss of enzyme activity are associated with severe, infantile Pompe disease, while mutations which allow partial enzyme expression are associated with adult onset disease. One very common mutation in intron 1 of the GAA gene, defined as c. The site of glycogen accumulation is different for all three forms of Pompe disease. Furthermore, the amount varies greatly in different organs and even in different muscles [ 51 ]. Histological examination of muscle will reveal large glycogen-filled vacuoles as well as freely dispersed glycogen outside the lysosomes. As lysosomes accumulate with glycogen, cell function becomes impaired. Mutation analysis is now the preferred method of diagnosis. Enzymatic studies can be performed, however, on muscle tissue or fibroblasts. It is imperative that α -1,4-glucosidase, also known as acid maltase due to its optimum pH lying between 4. Acid maltase is initially an inactive enzyme that is transported to the prelysosomal and lysosomal compartment via the mannosephosphate receptor [ 52—54 ]. The enzyme is eventually processed into a fully active form that normally degrades glycogen that enters lysosomes via autophagy. Deficiency of enzyme causes glycogen to overload the lysosomal system and leads to progressive and irreversible cellular damage. Before the advent of enzyme replacement therapy, treatment was generally supportive in nature and respiratory insufficiency was treated with assisted ventilation. For patients with juvenile Pompe disease, dysarthria and dysphagia caused by severe weakness of the facial muscles might necessitate feeding by G-tube. A high-protein diet, particularly a high-protein diet fortified with branched-chain amino acids, is recommended to help diminish catabolism of muscle protein. In , enzyme replacement therapy ERT became a commercially available option [ 55 ]. Myozyme ® alglucosidase alfa is indicated for use in patients with infantile-onset Pompe disease and has been shown to improve ventilator-free survival. In contrast, for patients who are eight years and older and do not have an enlarged heart, Lumizyme ® alglucosidase alfa is available and may help to preserve respiratory function and walking ability. ERT has proven to be less effective in the infantile Pompe patients than in the other populations. Since most people with the infantile form have no enzyme activity, the enzyme is recognized as foreign by the body, and a robust immune response develops against the ERT. Immunosuppression may help blunt this response and increase efficacy. Gene therapy using AAV-8 injected into the diaphragm is also being attempted in humans with the disease [ 59 ]. Glycogen storage disease type IIb Danon Disease OMIM is a multisystem disorder characterized by hypertrophic cardiomyopathy, heart arrhythmias, skeletal myopathy, retinal abnormalities, and variable degree of mental retardation [ 60—63 ]. Disease onset typically occurs in adolescence, with rapid progression toward end-stage heart failure in early adulthood [ 62 ]. Although the disease was initially classified as a glycogen storage disorder, glycogen is not always elevated in patients [ 64 ]. The biochemical hallmark of the disease is the accumulation of pathologic vacuoles containing glycogen or intermediary metabolites, mainly in skeletal and myocardial muscle with no evidence of enzyme deficiency. Danon disease is quite rare and good estimates of the incidence are not available. The disorder is X-linked dominant in nature and is due to LAMP-2 lysosome-associated membrane protein-2 deficiency. Although biochemical analysis is possible in male patients, diagnosis in females requires DNA mutation analysis [ 65 ]. Over fifty different mutations in the LAMP-2 gene have been identified [ 19, 66 ]. Glycogenoses types III and IV are clinically heterogeneous disorders caused by buildup of abnormally structured glycogen in the liver and muscle. Glycogen storage disease type III Cori disease or Forbes disease OMIM was initially discovered in when a patient being followed by Dr. Gilbert Forbes was found to have excessive amounts of abnormally structured glycogen in liver and muscle tissue [ 67, 68 ]. Type III GSD varies widely in clinical presentation and can be divided into two types: type IIIa, with both hepatic and muscle involvement, and type IIIb, which primarily presents with liver disease [ 69 ]. Both GSD IIIa and GSD IIIb result from an enzyme deficiency in the glycogen debranching enzyme GDE. This enzyme is encoded by the AGL gene located on chromosome 1p GSD type III is a phenotypically heterogeneous disorder with a wide clinical spectrum. While patients with GSD type IIIb mainly present with hepatic findings, affected individuals with type IIIa have both liver and muscle involvement. For both IIIa and IIIb, liver disease predominates in infancy and early childhood including hepatomegaly, hypoglycemia, hyperlipidemia, and growth retardation. Mild hypotonia and delayed motor development are usually the only manifestation during early childhood. By late childhood and adolescence, decreased stamina and pain with exertion can be noted. Muscle wasting is slowly progressive in adulthood and may be severe by the 3rd or 4th decade of life [ 70 ]. Although ventricular hypertrophy is a frequent finding, symptomatic cardiomyopathy leading to death is relatively rare. Unlike muscle disease which is a progressive process, the hypertrophic cardiomyopathy is reversible and appears to be due to excessive storage of glycogen. With a diet restricting intake of simple sugars, the hypertrophic cardiomyopathy can resolve and cardiac function normalize [ 71, 72 ]. Childhood hepatic symptoms tend to become milder with age. Complications aside from the myopathy are rare. Cirrhosis can also develop in patients with GSD III, and rare cases of hepatocellular carcinoma have been reported [ 73, 74 ]. Unlike in GSD Ia, hepatocellular carcinoma can develop anywhere in the liver, and it is not the result of malignant transformation of a hepatic adenoma [ 23 ]. Although all individuals with GSD type III show liver involvement, in rare instances the hepatic symptoms are mild and the diagnosis is not made until adulthood when individuals show signs of neuromuscular disease. Other clinical findings include abnormal nerve conduction studies and osteoporosis. Successful pregnancies have been reported. GSD Types IIIa and IIIb are autosomal recessive allelic disorders caused by mutations in the AGL gene on the short arm of chromosome 1 [ 75 ]. The incidence of GSD III is estimated to be 1 in , live births, but high risk populations have been identified. GSD IIIa is also more common on the Indian subcontinent India, Pakistan, Afghanistan. To date, at least different pathogenic AGL mutations have been reported [ 19 ]. The encoded enzyme, glycogen debranching enzyme GDE , together with glycogen phosphorylase, is responsible for the complete degradation of glycogen. GDE has a presumed glycogen binding site at the carboxy terminal end, as well as two separate sites responsible for independent catalytic activities. These activities include 4- α -glucanotransferase activity 1,4- α -D-glucan:1,4- α -D-glucan 4- α -D glycosyltransferase activity responsible for the transfer of three glucose units to the outer end of an adjacent chain, and an amylo-1,6-glucosidase activity responsible for hydrolysis of branch point glucose residues. The variable phenotype seen in GSD type III is partly explained by differences in tissue-specific expression. When the enzyme is deficient in both liver and muscle, GSD type IIIa results; in contrast, when AGL is deficient only in the liver and enzyme activity is retained in muscle, then GSD type IIIb results. Rare cases have also been reported where only one of two GDE catalytic activities is lost [ 79—81 ]. When there is loss of only glucosidase activity, the patient is classified as having GSD Type IIIc, and when there is only loss of transferase activity, the patient is classified as having GSD type IIId. While glycogenolysis is impaired in GSD III, gluconeogenesis is intact allowing lactate, amino acids, and glycerol from fatty acid oxidation to be used to maintain blood glucose concentrations. Protein is used as the primary source of energy in GSD type III since it also can be used directly by the muscles and has been associated with improvement in the myopathy. The frequency of cornstarch doses varies with age. In infancy, frequent cornstarch administration may be required with therapy similar to that used in GSD type I. With older children and adults, cornstarch frequently is only required times per day, and sometimes it is only administered prior to bedtime. For patients with moderate to severe hypertrophic cardiomyopathy, a high-protein nocturnal enteral therapy may be beneficial. Intake of simple sugars is limited to 5 grams per meal to minimize postprandial hyperinsulinemia and avoid over-storage of glycogen. Glycogen storage disease type IV Andersen disease OMIM and Adult Polyglucosan Body Disease APBD OMIM are allelic disorders caused by a deficiency of the glycogen branching enzyme encoded by the GBE1 gene. GSD type IV is quite rare, representing 0. GSD type IV shows significant variability in terms of age of onset and extent of organ and tissue involvement [ 82—85 ]. In its common classic form, patients have failure to thrive and hepatosplenomegaly. Portal hypertension and ascites develop, and progressive cirrhosis often occurs in early childhood. Without a liver transplant, death usually occurs by five years of age. Unlike the other liver forms of GSD, hypoglycemia is a late manifestation of GSD IV. Neuromuscular forms of GSD type IV are quite variable and may be classified into several different phenotypes; interestingly, they represent the most severe and the most mild forms of GSD type IV. The most severe and relatively rare form of GSD type IV presents perinatally as fetal akinesia deformation sequence with arthrogryposis, hydrops, polyhydramnios, and pulmonary hypoplasia. In this form of the disease, death occurs at an early age due to cardiac or pulmonary insufficiency. Other severe forms of neuromuscular GSD type IV present congenitally or in early infancy with hypotonia and skeletal muscle atrophy. Prognosis varies for these forms of the disease, usually depending on the extent of cardiac and hepatic involvement. Finally, in its milder forms, GSD type IV may present in late childhood, adolescence, or even adulthood as myopathy or adult polyglucosan body disease APBD with central and peripheral nervous system dysfunction [ 85 ]. APBD is an allelic variant of GSD Type IV characterized by adult-onset progressive neurogenic bladder, gait difficulties due to spasticity and weakness, distal lower extremity sensory loss, and mild cognitive difficulties OMIM [ 86 ]. GSD type IV is the result of a deficiency of glycogen branching enzyme which is encoded by the GBE1 gene located on chromosome 3p This gene is the only gene known to be associated with GSD type IV. Deficiency or absence of the encoded enzyme leads to excessive deposition of abnormally-structured, amylopectin-like glycogen in affected tissues. Because the accumulated glycogen lacks multiple branch points, it has poor solubility and causes irreversible tissue and organ damage. Residual enzyme activity may confound the results of enzyme analysis; therefore, mutation analysis is often recommended to confirm the diagnosis. Thus far, at least thirty-nine different mutations have been reported across the entire length of the gene, including nonsense, missense, splice site changes, micro insertions and deletions, and several gross deletions spanning multiple exons [ 19 ]. At present, there does not appear to be a strong genotype-phenotype correlation, and patients with the same mutation may show a wide range of clinical severity. In general, patients with two missense mutations have a milder form of disease than individuals with two null mutations. There is one GBE1 exon 7 missense variant that is predicted to result in the amino acid substitution p. While the hepatic scarring is the most severe of the glycogenoses, hepatic transaminase elevation is variable. Hepatic dysfunction occurs as the disease progresses. Creatine kinase levels range from normal to very elevated, and electromyography may show diffuse fibrillations. GSD type IV is characterized by amylopectinosis. Histologic examination of liver tissue reveals periodic acid-Schiff PAS -positive, diastase-resistant intracytoplasmic inclusions consistent with abnormal glycogen. Characteristic findings in hematoxylin and eosin stained liver tissue include distorted hepatic architecture with diffuse interstitial fibrosis and wide fibrous septa surrounding micronodular areas of parenchyma. Hepatocytes are generally two to three times normal size with basophilic cytoplasmic inclusions. Electron microscopy of affected tissue reveals normal glycogen particles plus abnormal fibrillary aggregates typical of amylopectin polyglucosan bodies. Muscle fibers from affected patients demonstrate severe depletion of myofibrils, and there may be amyloplasia with total fatty replacement of skeletal muscle. Polyglucosan bodies are invariably seen which are resistant to diastase digestion. In contrast to classical GSD type IV, the pathologic hallmark of adult polyglucosan body disease is the widespread accumulation of round, intracellular polyglucosan bodies throughout the nervous system, which are confined to neuronal and astrocytic processes [ 89 ]. Treatment of GSD IV is typically supportive. A high protein diet may have some benefit, but it has not prevented progression of the liver disease. Cornstarch is beneficial if hypoglycemia is occurring, but it similarly does not change the natural history of the disease. Due to the poor prognosis, liver transplantation remains the primary treatment for the child with early-onset, classic hepatic presentation. Individuals with adult-onset APBD may require antispasmodic bladder medications or bladder catheterization. Gait assist devices may also help to minimize the risk of falls [ 86 ]. Glycogen storage diseases types V McArdle Disease and VI Hers Disease are the result of a deficiency of glycogen phosphorylase, while glycogen storage disease Type IX is due to deficiency of phosphorylase b kinase, the activating enzyme of glycogen phosphorylase. Glycogen phosphorylase enzyme catalyzes the rate-limiting step in glycogenolysis and shows tissue-specific expression, with different forms of the enzyme being expressed in liver and muscle. Glycogen storage disease type V OMIM is a pure myopathic form of GSD affecting skeletal muscle. This disease was the first metabolic myopathy to be recognized and was described by Dr. Brian McArdle in after studying a young man with exercise intolerance and muscle cramps [ 91 ]. The clinical severity of McArdle disease is highly variable. Virtually all people with GSD V describe lifelong exercise intolerance, but the diagnosis is not usually made until the second to third decade of life when cramping becomes more prominent. Patients present with exercise-induced fatigue, painful muscle cramps, myalgia, and myoglobinuria. Diagnosis can be made by demonstration of failure of venous lactate to rise with an ischemic forearm test or following exercise. Electromyography does not demonstrate specific abnormalities. In , Vissing and Haller published a diagnostic test for McArdle disease based on moderate cycle exercise [ 92 ]. The authors noted that in contrast to patients with other metabolic myopathies, McArdle disease patients show decreased heart rate 7 to 15 minutes into moderate, constant-workload aerobic activity. McArdle disease results from a deficiency of muscle-expressed glycogen phosphorylase, or myophosphorylase [ 93, 94 ]. Myophosphorylase is encoded by the PYGM gene on the long arm of chromosome 11 [ 95, 96 ]. The gene is comprised of 20 exons, and over mutations have been described [ 19, 97—99 ]. Two mutations, Arg50Stop R50X in exon 1 which also has been commonly reported in the research literature as R49X and GlySer in exon 5 are common mutations in patients with European heritage [ 91, ]. Although no strict genotype-phenotype correlations have been made, there have been reports of more severe phenotypes in patients homozygous for both R50X mutations in PYGM and Q12X mutations in the AMPD1 gene encoding muscle adenylate deaminase [ , ]. Cases of muscle symptoms in heterozygous carriers have been reported [ ]. Enzyme studies on muscle biopsy will reveal absence of myophosphorylase in muscle fibers. Microscopy may also reveal acid-Schiff stained glycogen. Because the metabolic block in McArdle disease impairs glycogen breakdown but glucose utilization remains intact, patients with GSD type V benefit from glucose or sucrose loading before exercise [ , ]. Intense exercise should be avoided as it can lead to rhabdomyolysis with concomitant myoglobinuria and renal failure. Statin usage is contraindicated, and it should be noted that even heterozygous carriers may show adverse side effects to these medications [ ]. Oral vitamin B 6 has been reported to impart greater resistance to fatigue, and a high protein diet may also help [ ]. Glycogen storage disease type VI Hers disease OMIM was reported by Henry-Gery Hers in [ ]. This disorder is the result of a deficiency of liver glycogen phosphorylase, which is encoded by the PYGL gene located on chromosome 14q22 [ ]. Patients present in infancy or early childhood with varying degrees of growth retardation and prominent hepatomegaly secondary to excessive liver glycogen. Ketotic hypoglycemia or just hyperketosis occur with prolonged fasting or strenuous exercise [ ]. Because gluconeogenesis is preserved, hypoglycemia tends to be mild. Hypotonia may lead to delayed motor development even though there is no intrinsic muscle involvement. Mild hyperlipidemia is common, and liver function tests may reveal elevated serum transaminases. Unlike other types of GSD, lactic acid and uric acid concentrations are normal. While patients with GSD VI have a milder course with few complications, treatment improves growth, stamina, and normalizes the biochemical abnormalities. Rarely, liver fibrosis develops in GSD VI, and a cardiomyopathy can occur from over storage of carbohydrate [ ]. Most adults are asymptomatic, but adult females may experience hypoglycemia during pregnancy or with alcohol consumption. The enzyme exists as a homodimer of the PYGL protein and requires pyridoxal phosphate PLP as a cofactor. The enzyme switches between an active conformation GP a and an inactive conformation GP b , with activation dependent upon phosphorylation of a serine located at amino acid position Such phosphorylation occurs in response to the hormones glucagon and epinephrine. GSD type VI is inherited in an autosomal recessive fashion. The PYGL gene on chromosome 14 spans over 39, base pairs, consists of 20 coding exons, and encodes a protein that is amino acids in length [ ]. Thus far, thirty disease-causing mutations have been reported [ 19, — ]. The vast majority of pathogenic variants are missense mutations [ ]. No affected individuals have been described with two null alleles, suggesting that complete absence of liver glycogen phosphorylase activity may be incompatible with life. The estimated disease incidence ranges from 1 in 65, to 1 in 85, births, but many people with this condition are undiagnosed. In the Mennonite community, however, there is a founder mutation c. Although hepatic glycogen phosphorylase enzyme is expressed in several cell types and its activity can be assayed using erythrocytes, leukocytes, or hepatocytes, such testing is neither highly sensitive nor specific. False negative results are common because enzyme activity is significantly reduced in Hers disease but is never completely absent. False positive results also are not rare, because reduced liver phosphorylase activity may be due to mutations in the PYGL gene or mutations in several other genes including PHKA2 , PHKB , and PHKG2 that encode phosphorylase b kinase, the activating enzyme for hepatic glycogen phosphorylase. As a result, mutation detection is now the preferred method to differentiate liver phosphorylase deficiency from the much more common deficiency of the phsophorylase b kinase activating enzyme. Liver biopsies demonstrate glycogen filled hepatocytes with or without fibrosis, but DNA analysis or enzymatic testing is needed to differentiate GSD VI from the other forms of GSD. Affected individuals should avoid prolonged fasting, and eat frequent small meals. Uncooked cornstarch 1—4 times per day and protein supplementation may help stabilize blood glucose levels and prevent complications such as short stature, delayed puberty, and osteoporosis. Protein supplementation typically is lower than in GSD III 2—2. Rarely, cirrhosis and hepatocellular carcinoma can occur in Hers disease [ , ]. Patients should avoid excessive amounts of simple sugars. In addition, growth hormone therapy should not be used to treat short stature since it will lead to increased ketone production. To assess metabolic control, blood glucose levels and blood ketones should be routinely monitored. Height and weight measurements should also be assessed regularly since growth is normal when treatment is optimized. Because phosphorylase b kinase is required to activate the enzyme glycogen phosphorylase, GSD Types VI and IX show significant clinical overlap. Nevertheless, these two glycogenoses are very different disorders from a genetic standpoint, and this may have important implications for accurate genetic counseling and recurrence risk. GSD type IX has the most heterogeneous clinical picture of all of the glycogen storage diseases. Most patients are diagnosed after hepatomegaly is incidentally found, and it is the most common identifiable cause of ketotic hypoglycemia in males [ ]. While most patients are relatively mild, a severe variant exists that mimics type I GSD in infancy with severe fasting hypoglycemia. There is at least one form of GSD type IX which is strictly muscle-specific, and affected patients may present with muscle pain and weakness, exercise intolerance, and myoglobinuria. Another form of GSD type IX strictly presents as hepatic disease that typically begins in the first few months of life, and affected individuals may have ketotic hypoglycemia, hepatomegaly due to elevated glycogen content, liver disease, growth retardation, hypotonia, abnormal lipid profile, and increased lactate and uric acid. In its mildest hepatic form, patients may have a phenotype similar to GSD Type VI and symptoms may gradually subside with age. In patients with hepatic transaminase elevation, liver complications can develop including fibrosis, cirrhosis, adenomas, and hepatocellular carcinoma [ ]. Glycogen storage disease type IX is a genetically heterogeneous disorder. The phosphorylase kinase Phk enzyme is a hexadecameric structure comprised of four copies each of four different polypeptides, including alpha α , beta β , gamma γ , and delta δ subunits [ ]. To add to the molecular complexity, various tissue-specific isoforms exist for each subunit; these isoforms may be due to expression from separate genes or from alternative splicing of a single gene. α -associated GSD Type IX may result from mutations in one of two X-linked genes: PHKA1 or PHKA2. PHKA1 is located on the long arm of chromosome X at Xq13 while PHKA2 is located on the short arm of the X chromosome at Xp PHKA1 expression is confined to muscle, and therefore PHKA1 mutations are associated with exercise intolerance, muscle pain, weakness, and myoglobinuria [ — ]. To date, there are only seven reported mutations in the PHKA1 gene [ 19 ]. In contrast, PHKA2 gene expression is confined to liver and blood cells, and patients with PHKA2 mutations strictly have a hepatic presentation with ketotic hypoglycemia, hepatomegaly, chronic liver disease, retarded growth and motor development, and elevated lipids [ — ]. In contrast to the α -subunit, there is only one gene known to encode the β -subunit of the Phk enzyme. This gene, PHKB , is located on the long arm of chromosome 16 at 16q Alternative splicing of several exons gives rise to tissue-specific transcripts, and PHKB mutations have been associated with phosphorylase kinase enzyme deficiency in both liver and muscle [ — ]. Most mutations identified in PHKB have been severe null mutations expected to lead to premature protein truncation or mRNA decay; nevertheless, patients generally have mild symptoms including hypoglycemia after prolonged fasting, hepatomegaly, and mild hypotonia [ 19 ].
What are the types of GSD?	Much less common causes of hypoglycemia include read more and protrusion of the abdomen because excess or abnormal glycogen may enlarge the liver. Low levels of sugar in the blood cause sweating, confusion, and sometimes seizures and coma. Other consequences for children may include stunted growth, frequent infections, and sores in the mouth and intestines. Glycogen storage diseases tend to cause uric acid a waste product to accumulate in the joints, which can cause gout Gout Gout is a disorder in which deposits of uric acid crystals accumulate in the joints because of high blood levels of uric acid hyperuricemia. The accumulations of crystals cause flares attacks read more , and in the kidneys, which can cause kidney stones Stones in the Urinary Tract Stones calculi are hard masses that form in the urinary tract and may cause pain, bleeding, or an infection or block of the flow of urine. Tiny stones may cause no symptoms, but larger stones In type I glycogen storage disease, kidney failure is common at age 11 to 20 years or later. Glycogen storage disease is diagnosed by examining a piece of muscle or liver tissue under a microscope biopsy and by doing magnetic resonance imaging Magnetic Resonance Imaging MRI Magnetic resonance imaging MRI is a type of medical imaging that uses a strong magnetic field and very high frequency radio waves to produce highly detailed images. During an MRI, a computer read more MRI to detect glycogen in the tissues. Doctors confirm the diagnosis by analyzing the DNA. Glycogen storage disease type II Pompe disease is now part of the screening test for newborns Newborn Screening Tests Screening tests are done to detect health conditions that are not yet causing symptoms. Many serious disorders that are not apparent at birth can be detected by various screening tests. read more in many states. Other tests, such as liver, skin, muscle, and blood tests, are done to determine the specific type of glycogen storage disease. Genetic testing Genetic Screening Before Pregnancy Genetic screening is used to determine whether a couple is at increased risk of having a baby with a hereditary genetic disorder. Hereditary genetic disorders are disorders of chromosomes or read more to determine whether a couple is at increased risk of having a baby with a hereditary genetic disorder is also available. See also diagnosis of hereditary disorders of metabolism Diagnosis Hereditary metabolic disorders are inherited genetic conditions that cause metabolism problems. For most types, eating many small carbohydrate-rich meals every day helps prevent blood sugar levels from dropping. For people who have glycogen storage diseases that cause low blood sugar levels, levels are maintained by giving uncooked cornstarch every 4 to 6 hours around the clock, including overnight. For others, it is sometimes necessary to give carbohydrate solutions through a stomach tube all night to prevent low blood sugar levels from occurring at night. Liver Transplant. Glycogen Storage Diseases GSD in Children What Is Glycogen Storage Disease? Types of Glycogen Storage Disease The main types of glycogen storage diseases in children are categorized by number and name. Glycogen Storage Disease Symptoms Glycogen storage disease symptoms in pediatric patients depend on its type. These tests may include: Biopsy of the affected organs Blood tests and urine tests MRI scan — a test that uses magnetic waves to make pictures of the inside of the body Glycogen Storage Disease Treatment Glycogen storage disease treatment will depend on the type of disease and the symptoms. The goal of treatment is to maintain normal blood glucose levels. This may be done with: A nasogastric infusion of glucose in infants and children under age two Dietary changes, including: In children over age two, frequent small carbohydrate feedings are given throughout the day. This may include uncooked cornstarch. Uncooked cornstarch provides a steady slow-release form of glucose. Elimination of foods that are high in fructose or lactose type I only Allopurinol Aloprim, Zyloprim may be prescribed to reduce uric acid levels in the blood. This is done to prevent gout and kidney stones. Type IV is sometimes treated with liver transplantation. This is done by: Regulating or limiting strenuous exercise to avoid fatigue symptoms Improving exercise tolerance by oral intake of glucose or fructose fructose must be avoided in people with type I , or an injection of glucagon Eating a high protein diet There is no way to prevent glycogen storage diseases. Find a Doctor. Contact Us. Pay My Bill. Search by: Last Name Doctor Last Name Practice. Gender Male Female. Language Language Afrikaan Arabic Bengali Bosnian Bulgarian Burmese Cantonese Catalan Chinese Chinese Mandarin Creole Croatian Czech Dutch Farsi Filipino French Gaelic German Greek Gujarati Hebrew Hindi Hungarian Ibo Indian Italian Japanese Kannada Kashmiri Kikuyu Korean Latin Lebanese Lithuanian Malaysian Marathi Persian Polish Portuguese Punjabi Romanian Russian Sanskrit Serbian Sign Language Sindhi Sinhalese Spanish Sri-Lankan Swahili Swedish Tagalog Taiwanese Tamil Telugu Thai Turkish Ukrainian Urdu Vietnamese Yiddish Yoruba. Role Role Doctor Physician Assistant Nurse Practitioner. Pittsburgh, PA Get directions to our main campus. Search our locations. MyCHP: Manage your child's health information online - on your time! With MyCHP, you can request appointments, review test results, and more. Log-In to MyCHP Sign Up: Parents, legal guardians, and patients may sign-up online. The liver and sometimes the kidneys swell due to built-up glycogen. Glycogen storage disease type III GSD III , also known as Cori disease or Forbes disease, causes glycogen to build up in the liver and muscles. Symptoms typically appear within the first year of life. Children with this type of GSD may have a swollen belly, delayed growth , and weak muscles. Glycogen storage disease type IV GSD IV , also known as Andersen disease, is one of the most serious types of GSD. This type of GSD often leads to cirrhosis of the liver and can affect the heart and other organs as well. Infants with type I GSD I may have low blood sugar. This type of GSD can also lead to lactic acidosis, a buildup of lactic acid, which can cause painful muscle cramps. As they mature into adolescence, children with GSD I may have delayed puberty and weak bones osteoporosis. Other risks include:. Infants with type III GSD III may have low blood sugar and excess fat in their blood. As they get older, their livers may become enlarged. Children with this type of GSD are also at risk for:. Infants with Type IV GSD IV may not have low blood sugar, but they can develop early complications. Children who survive with GSD IV are at risk for the following complications:. GSD is an inherited disease. Children are born with GSD when both parents have an abnormal gene that gets passed on to one of their children. Children with GSD lack one of the enzymes responsible for making glycogen or converting glycogen to glucose. As a result, their muscles do not receive the fuel they need to grow and glycogen builds up in their liver and other organs. Diagnosis starts with a health history. The doctor will also do a physical exam and check for signs of an enlarged liver or weak muscles. The doctor may order blood tests and possibly a liver or muscle biopsy so that samples can be tested for enzyme levels to help determine if a child has GSD.
Glycogen storage diseases: Diagnosis, treatment and outcome	Clinicians Diabetic-friendly breakfast ideas encouraged to Satiety and energy levels Tetra Fish Species Profile reasons for the use of a particular strage or test, whether or not it stlrage in conformance with this guideline. Glycogen storage Diagnosks are a group of disorders in which stored glycogen cannot be metabolized into glucose to supply energy and to maintain steady blood glucose levels for the body. See inborn errors of carbohydrate metabolism for a full list of inherited diseases that affect glycogen synthesis, glycogen breakdown, or glucose breakdown. Toggle limited content width. Manzia T. All studies surveyed were carried out with the same mean coverage of the ES method xwhich suggests an appropriate mean coverage for ES.
Glycogen Storage Diseases (GSD) in Children	Children with this type of GSD are also at risk for:. Infants with Type IV GSD IV may not have low blood sugar, but they can develop early complications. Children who survive with GSD IV are at risk for the following complications:. GSD is an inherited disease. Children are born with GSD when both parents have an abnormal gene that gets passed on to one of their children. Children with GSD lack one of the enzymes responsible for making glycogen or converting glycogen to glucose. As a result, their muscles do not receive the fuel they need to grow and glycogen builds up in their liver and other organs. Diagnosis starts with a health history. The doctor will also do a physical exam and check for signs of an enlarged liver or weak muscles. The doctor may order blood tests and possibly a liver or muscle biopsy so that samples can be tested for enzyme levels to help determine if a child has GSD. There is currently no cure for GSD. After diagnosis, children with GSD are usually cared for by several specialists, including specialists in endocrinology and metabolism. Specific dietitians with expertise in this disease should be involved. Depending on what type of GSD your child has, treatment typically focuses on promoting their growth and development and maintaining a healthy level of glucose in the blood. Typically, doctors recommend small, frequent meals throughout the day. The meals should be low in sugar to prevent glycogen from building up in the liver. Uncooked cornstarch can help maintain a healthy blood-sugar level. In some cases, doctors may recommend a nasogastric tube or gastrostomy G tube that delivers a continuous supply of nutrition while the child is sleeping. Children with GSD IV may need a liver transplant if the disease progresses to cirrhosis or liver failure. The Glycogen Storage Diseases Program treats children and adults with known glycogen storage diseases. Learn more about Glycogen Storage Diseases Program. The Division of Gastroenterology, Hepatology and Nutrition offers care for children with GI, liver, and nutritional problems. Then it was discovered that ingesting uncooked cornstarch regularly throughout the day helped these children maintain a steady, safe glucose level. Cornstarch is a complex carbohydrate that is difficult for the body to digest; therefore it acts as a slow release carbohydrate and maintains normal blood glucose levels for a longer period of time than most carbohydrates in food. Cornstarch therapy is combined with frequent meals eating every two to four hours of a diet that restricts sucrose table sugar , fructose sugar found in fruits and lactose only for those with GSD I. Typically, this means no fruit, juice, milk or sweets cookies, cakes, candy, ice cream, etc. because these sugars end up as glycogen trapped in the liver. Infants need to be fed every two hours. Those who are not breastfed must take lactose-free formula. Some types of GSD require a high-protein diet. Calcium, vitamin D and iron supplements maybe recommended to avoid deficits. Children need their blood glucose tested frequently throughout the day to make sure they are not hypoglycemic, which can be dangerous. Some children, especially infants, may require overnight feeds to maintain safe blood glucose levels. For these children, a gastrostomy tube, often called a g-tube, is placed in the stomach to make overnight feedings via a continuous pump easier. The outlook depends on the type of GSD and the organs affected. With recent advancements in therapy, treatment is effective in managing the types of glycogen storage disease that affect the liver. Children may have an enlarged liver, but as they grow and the liver has more room, their prominent abdomen will be less noticeable. Other complications include benign noncancerous tumors in the liver, scarring cirrhosis of the liver and, if lipid levels remain high, the formation of fatty skin growths called xanthomas. To manage complications, children with GSD should been seen by a doctor who understands GSDs every three to six months. Blood work is needed every six months. Once a year, they need a kidney and liver ultrasound. Research into enzyme replacement therapy and gene therapy is promising and may improve the outlook for the future. CHOP will be a site for upcoming gene therapy clinical trials for types I and III. Other consequences for children may include stunted growth, frequent infections, and sores in the mouth and intestines. Glycogen storage diseases tend to cause uric acid a waste product to accumulate in the joints, which can cause gout Gout Gout is a disorder in which deposits of uric acid crystals accumulate in the joints because of high blood levels of uric acid hyperuricemia. The accumulations of crystals cause flares attacks read more , and in the kidneys, which can cause kidney stones Stones in the Urinary Tract Stones calculi are hard masses that form in the urinary tract and may cause pain, bleeding, or an infection or block of the flow of urine. Tiny stones may cause no symptoms, but larger stones In type I glycogen storage disease, kidney failure is common at age 11 to 20 years or later. Glycogen storage disease is diagnosed by examining a piece of muscle or liver tissue under a microscope biopsy and by doing magnetic resonance imaging Magnetic Resonance Imaging MRI Magnetic resonance imaging MRI is a type of medical imaging that uses a strong magnetic field and very high frequency radio waves to produce highly detailed images. During an MRI, a computer read more MRI to detect glycogen in the tissues. Doctors confirm the diagnosis by analyzing the DNA. Glycogen storage disease type II Pompe disease is now part of the screening test for newborns Newborn Screening Tests Screening tests are done to detect health conditions that are not yet causing symptoms. Many serious disorders that are not apparent at birth can be detected by various screening tests. read more in many states. Other tests, such as liver, skin, muscle, and blood tests, are done to determine the specific type of glycogen storage disease. Genetic testing Genetic Screening Before Pregnancy Genetic screening is used to determine whether a couple is at increased risk of having a baby with a hereditary genetic disorder. Hereditary genetic disorders are disorders of chromosomes or read more to determine whether a couple is at increased risk of having a baby with a hereditary genetic disorder is also available. See also diagnosis of hereditary disorders of metabolism Diagnosis Hereditary metabolic disorders are inherited genetic conditions that cause metabolism problems. For most types, eating many small carbohydrate-rich meals every day helps prevent blood sugar levels from dropping. For people who have glycogen storage diseases that cause low blood sugar levels, levels are maintained by giving uncooked cornstarch every 4 to 6 hours around the clock, including overnight. For others, it is sometimes necessary to give carbohydrate solutions through a stomach tube all night to prevent low blood sugar levels from occurring at night. People who have a glycogen storage disease that affects the muscles should avoid excessive exercise. The following are some English-language resources that may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
Glycogen Storage Disease Type I	The presence of fibrosis, glycogeb from Satiety and energy levels Fiber-rich foods for digestion fibrosis to micronodular pf, occurs in Storave Satiety and energy levels, GSD VI, and Sttorage IX but not in GSD I. Erez A. Disfase F. NORD gratefully acknowledges Deeksha Bali, PhD, Professor, Division of Medical genetics, Department of Pediatrics, Duke Health; Co-Director, Biochemical Genetics Laboratories, Duke University Health System, and Yuan-Tsong Chen, MD, PhD, Professor, Division of Medical Genetics, Department of Pediatrics, Duke Medicine; Distinguished Research Fellow, Academia Sinica Institute of Biomedical Sciences, Taiwan for assistance in the preparation of this report. An average of 8, variants was identified per patient. The system may also help detect asymptomatic hypoglycemia.

Diagnosis of glycogen storage disease -

TEXTBOOKS Chen YT, Bali DS. Prenatal Diagnosis of Disorders of Carbohydrate Metabolism. In: Milunsky A, Milunsky J, eds. Genetic disorders and the fetus — diagnosis, prevention, and treatment. West Sussex, UK: Wiley-Blackwell; Chen Y. Glycogen storage disease and other inherited disorders of carbohydrate metabolism.

In: Kasper DL, Braunwald E, Fauci A, et al. New York, NY: McGraw-Hill; Weinstein DA, Koeberl DD, Wolfsdorf JI. Type I Glycogen Storage Disease.

In: NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott, Williams and Wilkins; JOURNAL ARTICLES Chou JY, Jun HS, Mansfield BC.

J Inherit Metab Dis. doi: Epub Oct 7. PubMed PMID: Kishnani PS, Austin SL, Abdenur JE, Arn P, Bali DS, Boney A, Chung WK, Dagli AI, Dale D, Koeberl D, Somers MJ, Wechsler SB, Weinstein DA, Wolfsdorf JI, Watson MS; American College of Medical Genetics and Genomics.

Genet Med. Austin SL, El-Gharbawy AH, Kasturi VG, James A, Kishnani PS. Menorrhagia in patients with type I glycogen storage disease. Obstet Gynecol ;— Dagli AI, Lee PJ, Correia CE, et al.

Pregnancy in glycogen storage disease type Ib: gestational care and report of first successful deliveries. Chou JY, Mansfield BC. Mutations in the glucosephosphatase-alpha G6PC gene that cause type Ia glycogen storage disease.

Hum Mutat. Franco LM, Krishnamurthy V, Bali D, et al. Hepatocellular carcinoma in glycogen storage disease type Ia: a case series. Lewis R, Scrutton M, Lee P, Standen GR, Murphy DJ.

Antenatal and Intrapartum care of a pregnant woman with glycogen storage disease type 1a. Eur J Obstet Gynecol Reprod Biol. Ekstein J, Rubin BY, Anderson, et al.

Mutation frequencies for glycogen storage disease in the Ashkenazi Jewish Population. Am J Med Genet A. Melis D, Parenti G, Della Casa R, et al. Brain Damage in glycogen storage disease type I. J Pediatr. Rake JP, Visser G, Labrune, et al. Guidelines for management of glycogen storage disease type I-European study on glycogen storage disease type I ESGSD I.

Eur J Pediatr. Rake JP Visser G, Labrune P, et al. Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European study on glycogen storage disease type I EGGSD I.

Eur J Pediat. Chou JY, Matern D, Mansfield, et al. Type I glycogen Storage diseases: disorders of the glucosePhosphatase complex. Curr Mol Med. Schwahn B, Rauch F, Wendel U, Schonau E. Low bone mass in glycogen storage disease type 1 is associated with reduced muscle force and poor metabolic control.

Visser G, Rake JP, Labrune P, et al. Consensus guidelines for management of glycogen storage disease type 1b.

Results of the European study on glycogen storage disease type I. Weinstein DA and Wolfsdorf JI. Effect of continuous gucose therapy with uncooked cornstarch on the long-term clinical course of type 1a glycogen storage disease.

Eur J Pediatr ; Janecke AR, Mayatepek E, and Utermann G. Molecular genetics of type I glycogen storage disease. Mol Genet Metab.

Viser G, Rake JP, Fernandes, et al. Types of Glycogen Storage Disease The main types of glycogen storage diseases in children are categorized by number and name. Glycogen Storage Disease Symptoms Glycogen storage disease symptoms in pediatric patients depend on its type. These tests may include: Biopsy of the affected organs Blood tests and urine tests MRI scan — a test that uses magnetic waves to make pictures of the inside of the body Glycogen Storage Disease Treatment Glycogen storage disease treatment will depend on the type of disease and the symptoms.

The goal of treatment is to maintain normal blood glucose levels. This may be done with: A nasogastric infusion of glucose in infants and children under age two Dietary changes, including: In children over age two, frequent small carbohydrate feedings are given throughout the day.

This may include uncooked cornstarch. Uncooked cornstarch provides a steady slow-release form of glucose. Elimination of foods that are high in fructose or lactose type I only Allopurinol Aloprim, Zyloprim may be prescribed to reduce uric acid levels in the blood.

This is done to prevent gout and kidney stones. Type IV is sometimes treated with liver transplantation. This is done by: Regulating or limiting strenuous exercise to avoid fatigue symptoms Improving exercise tolerance by oral intake of glucose or fructose fructose must be avoided in people with type I , or an injection of glucagon Eating a high protein diet There is no way to prevent glycogen storage diseases.

Find a Doctor. Contact Us. Pay My Bill. Search by: Last Name Doctor Last Name Practice. Gender Male Female. Language Language Afrikaan Arabic Bengali Bosnian Bulgarian Burmese Cantonese Catalan Chinese Chinese Mandarin Creole Croatian Czech Dutch Farsi Filipino French Gaelic German Greek Gujarati Hebrew Hindi Hungarian Ibo Indian Italian Japanese Kannada Kashmiri Kikuyu Korean Latin Lebanese Lithuanian Malaysian Marathi Persian Polish Portuguese Punjabi Romanian Russian Sanskrit Serbian Sign Language Sindhi Sinhalese Spanish Sri-Lankan Swahili Swedish Tagalog Taiwanese Tamil Telugu Thai Turkish Ukrainian Urdu Vietnamese Yiddish Yoruba.

Role Role Doctor Physician Assistant Nurse Practitioner. Pittsburgh, PA Get directions to our main campus. Search our locations. MyCHP: Manage your child's health information online - on your time!

With MyCHP, you can request appointments, review test results, and more. Log-In to MyCHP Sign Up: Parents, legal guardians, and patients may sign-up online. Parents, legal guardians, and patients may also sign-up in person during a hospital stay, at a clinic appointment, or by visiting the UPMC Health Plan Connect Service and Sales Center at your local mall.

Learn More. Complete G6PC sequencing is usually performed first, unless neutropenia is present. If snap-frozen liver biopsy tissue is available to confirm the diagnosis, it can be analyzed for G6Pase enzymatic activity.

Deficient enzyme activity confirms the diagnosis of GSD Ia. Other specialists required to manage specific manifestations of the disease include a nephrologist, a hepatologist, a hematologist, a genetic counselor, and a cardiologist.

All specialists involved in the care of an individual with GSD I should have an understanding of the disease, its protean manifestations, and its unique challenges, including the psychological and emotional impacts of this disease on patients and families.

The defect of G6Pase and translocase greatly impacts the nutrition status of those with GSD I. Nutrition therapy for GSD Ia and GSD Ib is the same, but those with GSD Ib may require further dietary intervention related to the consequences of neutropenia such as Crohn disease—like enterocolitis.

Hypoglycemia—the primary concern in infants and young children with GSD I—permeates all aspects of their diet and lifestyle although in rare cases older children or adults with GSD I may present without hypoglycemia see Box 2.

Children who are fed frequently from birth may not exhibit obvious signs of hypoglycemia until they sleep through the night or have an illness and fast for an extended period of time. Once a diagnosis is made and nutrition therapy is implemented, close BG monitoring and other laboratory parameters must continue as the child grows and nutritional needs change.

Without frequent BG monitoring, asymptomatic low BG levels result in suboptimal control, which further inhibits normal growth, development, and overall metabolic control. Nutrition therapy. Recurrent hypoglycemia causes lactic acidosis, hepatomegaly, hypertriglyceridemia, hyperuricemia, and failure to thrive in the young child.

Thus, avoidance of fasting is the first line of treatment in GSD I. To prevent hypoglycemia, small frequent feedings high in complex carbohydrates preferably those higher in fiber are evenly distributed over 24 hours.

Careful assessment and supplementation of micronutrients is required to avoid nutrient deficiencies. Formulas and enteral feedings. In infancy, a soy-based, sugar-free formula or a formula that is free of sucrose, fructose, and lactose is fed on demand every 2—3 hours.

Once the infant is able to sleep longer than 3—4 hours at a time, several decisions must be made to avoid hypoglycemia during the overnight fast. One option is to continue to wake the infant every 3—4 hours to monitor BG and offer feedings. Another option is to use overnight gastric feedings OGFs.

For patients with GSD Ib and neutropenia, a G-tube may not be a good option because of the risk for recurrent infections at the surgical site.

If a child has neutropenia, a G-tube should be placed only if granulocyte colony-stimulating factor G-CSF Neupogen is being administered. Formulas for the OGF may be the same infant formula the child uses during the day should be sucrose free, fructose free, and lactose free or it may be an elemental formula that has a higher percentage of carbohydrates.

Infusing glucose may be an option in some cases. Feeding regimens are determined case by case. When the tube feeding is completed each morning, there will still be high circulating insulin levels.

OGFs are not without fault or risks. There have been reports of pump failures and occluded or disconnected tubing preventing the formula from being infused and leading to hypoglycemia, seizures, and even death. Introducing solid food.

Solid food is introduced along the normal time line between 4 and 6 months of age. Infant cereals are followed by vegetables and then by meat. Fruits, juice, and other sucrose-containing, fructose-containing, and lactose-containing foods are limited or omitted.

Spoon-feeding, drinking from a cup, and the introduction of table foods should follow the normal feeding progression in order to prevent long-term feeding disorders. Any delays in this progression should be addressed immediately see later section on feeding issues. Restricting fruit, juice, and dairy foods impacts two entire food groups and renders the diet inadequate.

In GSD I, a complete multivitamin with minerals is essential. If a sugar-free soy-based milk that is fortified with calcium and vitamin D is not included, then calcium with vitamin D supplements are also essential. Without appropriate supplements, these children are at risk for a variety of nutritional deficiencies.

Although the cause may be multifactorial, optimal nutrition at a young age can only help prevent or delay some of the long-term consequences of the disease.

Therefore, the focus of the diet Table 4 must go beyond simply preventing and treating hypoglycemia. Cornstarch Raw cornstarch CS has been used for the treatment of hypoglycemia in GSD I since the early s.

Amylase is needed for the digestion of CS; this enzyme may or may not be fully present until 2 years of age.

Starting with a small dose of raw, uncooked CS and gradually increasing the dose to the goal may help improve tolerance. Side effects of CS may include gas, bloating, and diarrhea, but in some cases the symptoms may subside after 2 weeks of therapy.

General guidelines for dosing CS include 1. com brand CS, by patient report, is the preferred brand in the United States in terms of both taste and sustainability.

Other brands should be used with caution, and randomly switching between brands is not recommended. A modified CS, Glycosade, is available in Europe and the United States for overnight treatment. As with any changes to CS brand or dose, changes should be made under the supervision of the metabolic team with frequent BG monitoring.

In previous studies, mixing CS with lemonade or hot water or taking high doses of vitamin C resulted in a sharp increase in BG levels, followed by a rapid decline. It was speculated that the heating process and the ascorbic acid disrupted the starch granules, rendering the CS less effective.

The mechanism is likely similar to that described above for lemonade. Until further studies are available to investigate this mechanism, patients should not mix Bicitra with their CS drink. Ideally, the CS dose should be weighed on a gram scale. When a scale is not available, the dose may be translated into tablespoons.

The amount of fluid can be adjusted based on preference or tolerance. As with the OGF, CS therapy also has its limitations.

Missed CS doses because of failure of alarm clocks or sleeping through an alarm can lead to hypoglycemia, seizure, and even death. Parents may need to alternate nightly duties to avoid sleep deprivation that can lead to lapses. BG monitoring is essential for well-controlled GSD. Frequent BG monitoring is needed to establish the initial diet prescription and then should occur randomly to avoid asymptomatic hypoglycemia.

BG testing should be documented before each clinic visit so that diet, CS intake, and OGFs can be adjusted. A detailed record noting the time, the BG level, and all foods, CS, and beverages consumed should be provided to the clinic dietitian. Other changes to routines, school schedules, activities, or those at the onset of illness also require close BG monitoring.

Lactate meter. The use of a portable lactate meter LactatePro has been studied and used for the GSD population by at least one group in the United States and in Europe.

The lactate meter may be a good supplement to glucose monitoring, especially during times of illness to help prevent acute deterioration, to avoid hospitalization, or to alert the parent that is time to go to the emergency room. The lactate meter has been found more useful in GSD Ia as compared with GSD Ib in one study.

Continuous blood glucose monitoring system. Another tool that is often considered for monitoring and managing BG control in GSD is the continuous glucose monitoring system.

However, this may change with the development of new meters. The use of continuous glucose monitoring systems in the home environment under real-life circumstances may provide more realistic data and may show trends more clearly than in measurements made in the hospital setting.

The system may also help detect asymptomatic hypoglycemia. Signs of low glucose may include lethargy, muscle weakness, nausea, irritability, or a sense of lightheadedness or sweating. Treatment for hypoglycemia is twofold. First, the low BG must be rescued with a quick-acting source of glucose.

Then, a snack or CS is given in order to sustain normal BG. Treatment agents include commercially prepared glucose polymers or over-the-counter diabetic glucose tablets and gels. The amount of glucose given is determined based on the glucose delivery rate desired. All people with GSD I should wear a medical alert bracelet because prompt and appropriate treatment is critical in GSD I.

Continual episodes of hypoglycemia indicate an underlying problem. It may be time to adjust the CS dose or schedule. There may be an intercurrent illness or there may be a compliance factor. Parents fearing the known consequences of hypoglycemia may overcompensate by overtreating and overfeeding their child.

Parents should be cautioned against overtreatment at each clinic visit, especially if an increased weight trend is noted.

Other complications of overfeeding, including increased glycogen storage, over time can lead to hyperinsulinemia and insulin resistance. Increased gastrointestinal disturbances may also result from excess CS. Scheduling CS and balancing meals can be difficult and the metabolic dietitian should work closely with the family early on to avoid the development of feeding issues.

With most chronic illnesses that involve dietary treatment, it may be difficult for the family to achieve an appropriate balance. Children may be delayed making the transition from formula to baby food and from baby food to table food.

They may be delayed in weaning from the bottle to a cup. The child may be too full from formula and CS and refuse to take solid foods.

The metabolic dietitian will need to address these issues by periodically assessing the diet and adjusting the meal and snack schedules, CS doses, meal times, and OGFs.

If a child continues to show signs of difficulty with feeding, the child should be referred to a speech or occupational therapist for a full feeding evaluation. In some cases, if psychosocial issues are apparent, the family may be referred to the clinical social worker or the child may need a full psychological evaluation.

Changes in growth trends may reflect poor metabolic control. If revisions to the diet, CS, and OGFs do not improve growth, a referral to an endocrinologist may be indicated. In the older child who has a delayed bone age, the length needs to be corrected accordingly on the growth chart.

Otherwise, the child may be misdiagnosed with poor growth. Successful pregnancies in both GSD Ia and GSD Ib have been reported in the literature. Close BG monitoring is required so that diet and CS dosing and frequency can be adjusted.

CS requirements typically increase during pregnancy. The metabolic team and a high-risk obstetrics group should coordinate care together. The admission should be planned in advance so an i. glucose infusion can be initiated before delivery to maintain normal BG levels.

Good metabolic control also decreases the bleeding complications that could occur at the time of labor and delivery if poor metabolic control is a factor see Hematology section. Those with GSD I are at an increased risk for osteoporosis.

Good metabolic control, including adequate nutrients throughout the life span, may help prevent or delay bone loss. DEXA scans and OH vitamin D are included as part of the standard screening for GSD I. Gout is another long-term complication of GSD I.

Again, diet adherence and good metabolic control from the onset may prevent the high levels of uric acid that can cause gout. For those with a tendency toward gout attacks, a low-purine diet is prescribed in addition to allopurinol.

The side effects of allopurinol should be monitored, including hypersensitivity syndrome and Stevens—Johnson syndrome. Elevated triglycerides and cholesterol above the normal ranges may persist in some patients with GSD I, despite appropriate dietary treatment.

Although effects of hyperlipidemia in GSD I have been studied for decades, there is no consensus regarding the long-term complications or the best treatment for hyperlipidemia in this disorder.

Both dietary and pharmacological treatments have been studied, including fibrates, statins, niacin, and fish oil. In conclusion, dietary therapy for the treatment of GSD I has improved the long-term outcomes for patients, but, unfortunately, many complications remain.

Further studies of dietary practices and alternative dietary treatments are needed to provide consensus for evidence-based guidelines. Hepatomegaly in GSD I attributable to fat and glycogen deposition is universal, resulting in a marked steatotic and enlarged liver.

Given that the stored glycogen is normal in structure, liver enzymes are typically normal in GSD I. An elevation of liver enzymes may sometimes be noted early in the disease course, typically around the time of diagnosis. Hepatocellular adenoma HCA , HCC, hepatoblastoma, focal fatty infiltration, focal fatty sparing, focal nodular hyperplasia, and peliosis hepatis are some of the liver lesions noted in GSD Ia patients.

The prevalence of HCAs increases with age in GSD I. Adenomas noted in patients with GSD I are different than those that are noted in the general population. GSD Ia patients seem to present with greater numbers of HCAs that are more likely to be in a bilobar distribution than those in the general population.

Furthermore, unlike in the general population, there is no gender predisposition in GSD I. One study noted that of 66 HCAs detected by magnetic resonance imaging in 14 patients, 44 lesions were found in 5 patients, with a mean of 5 lesions per GSD I patient.

A recent study demonstrated decreased adenoma formation in the setting of good metabolic control, and regression of adenomas has occurred in some patients after outstanding metabolic control was achieved. Because patients with GSD I live longer, new long-term complications are being recognized.

HCC has been noted in several patients with GSD I. There are several challenges concerning the diagnosis of HCC in GSD I. The cause for HCC is unclear, but there appears to be an adenoma-to-HCC transformation, rather than HCC arising in normal liver tissue. Because of the abundance of adenomas, biopsy is not an option.

There is no effective biomarker because α-fetoprotein and carcinoembryonic antigen levels are often normal even in the setting of HCC. No good imaging tool separates HCA from HCC.

Until recently, the genetic makeup of the adenomas from patients with GSD I was not known. However, Kishnani et al. Although loss of 6q without gain of 6p was identified in two non-GSD I HCA general population HCAs in this study, and simultaneous gain of 6p and loss of 6q has been reported in two general population HCAs in a previous report, the significance of loss of 6q for HCA development in the general population was inconclusive because the aberration was just one of multiple chromosomal aberrations in these cases.

It is speculated that GSD I HCA with simultaneous gain of 6p and loss of 6q could confer high risk for malignant transformation, implicating genes on chromosome 6 in the transformation of HCA to HCC.

Patients with these high-risk aberrations may be good candidates for LT until we have a better understanding of the pathogenesis and other therapeutic targets.

These findings also suggest that good metabolic control alone may be insufficient to prevent the development of HCA in some patients with GSD I. In the general population, HCAs regress in some patients after the cessation of oral contraceptives. In GSD I, there is some evidence that metabolic control may be a modifier of adenoma formation and progression, but there are cases in which adenomas occur despite good metabolic control.

Whereas most investigators agree that HCAs in GSD Ia patients should be observed for signs of malignancy, the management of concerning lesions is not established. Liver imaging is routinely performed in individuals with GSD I.

With increasing age, computed tomography or magnetic resonance imaging scanning using i. contrast should be considered to look for evidence of increasing lesion size, poorly defined margins, or spontaneous hemorrhage.

contrast to minimize the number of missed lesions is recommended. It is also known that α-fetoprotein and carcinoembryonic antigen levels do not predict the presence of HCAs or malignant transformation 24 , in patients with GSD I see next section.

Initially, the management of liver adenomas in the GSD I population should be conservative Box 3. An approach of watchful waiting may be used. There are reports of the use of percutaneous ethanol injection as the initial treatment of enlarging liver adenomas.

Resection of HCAs suspected of being malignant is an effective intermediate step in the prevention of HCC in GSD Ia patients. As such, adenoma resection may be used as the initial management of lesions suspicious for malignancy in GSD I.

A study by Reddy et al. In this study it was noted that GSD Ia patients present with a greater burden of adenomatous disease and shorter progression-free survival after resection than the general population. This experience of HCA resection in GSD Ia patients demonstrates that partial hepatectomy is feasible in these patients and is an effective intermediate step in the prevention of HCC until definitive treatment such as a LT.

Because of the low numbers, the true risks of partial hepatectomy particular to this population have not been explored. Liver replacement is the ultimate therapy for hepatic metabolic disease.

It should be considered for patients with multifocal, growing lesions that do not regress with improved dietary regimens and who do not have evidence of distant metastatic disease. The first reported LT for GSD I was performed in ref However, there are several obstacles to LT in GSD Ia patients.

These include uncertainties regarding timing of transplantation, limited organ availability, prospects of worsening renal function with immunosuppression, and fears of poor patient compliance with immunosuppressive medication given a history of faulty adherence to a strict dietary regimen.

This score is calculated using a logarithmic assessment of three objective and reproducible variables, namely total serum bilirubin and creatinine concentrations, and the international normalized ratio.

The score may range from as low as 6 to a high of A MELD score of 15—17 is significant in that this is the point at which the mortality risk associated with liver disease and its complications is equivalent to the 1-year mortality associated with complications arising from LT.

In GSD I, because the hepatic abnormalities are the result of a single-gene, cell-autonomous defect, there is no possibility of recurrence of primary liver disease within the transplanted allograft.

The most common indication for liver transplantation in GSD I has been hepatic adenomatous disease for removal of potentially premalignant lesions. Other indications have included growth failure and poor metabolic control. Transplantation should be reserved for patients who have not had success with medical management, have a history of recurrent adenomas despite liver resection, have a rapid increase in the size and number of liver adenomas, and are at high risk for liver cancer.

Although the survival rate after transplantation has improved over the past 20 years, complications in the postoperative course remain. Chronic renal failure is a well-documented complication of liver transplantation in GSD Ia, and some patients with GSD Ia have progressed to renal failure within a few years of transplantation.

Alternatively, a primary GSD-related nephrotoxic effect may be present because of the untreated condition in the kidney. Postoperative pulmonary hypertension has also been documented in a small number of patients after transplantation. Although hypoglycemia similarly abates when liver transplantation is performed in GSD Ib, the neutropenia, neutrophil dysfunction, and Crohn disease—like inflammatory bowel disease are variably affected by liver transplantation.

G-CSF is still often needed to treat the neutropenia associated with GSD Ib despite normalization of the metabolic profile after liver transplantation because neutropenia is primarily attributable to an intrinsic defect in the neutrophils of GSD Ib patients and is not corrected by LT.

Renal manifestations of GSD I appear early in childhood and often go undetected without specific diagnostic evaluation.

Glycogen deposition occurs in the kidneys, which typically are large on renal imaging; however, nephromegaly is not sufficient to be readily detected on physical examination.

As a result of both the metabolic perturbations that arise and the glycogen accumulation with GSD I, there can be not only proximal and distal renal tubular dysfunction but also progressive glomerular injury that can result in functional renal impairment and even end-stage renal disease requiring renal replacement therapy.

Specific interventions aimed at ameliorating or trying to prevent the progression of these renal consequences of GSD I are best commenced early after their presentation to have the best opportunity to alter the course of renal injury. The proximal tubule is the site of a great deal of energy expenditure and G6Pase activity is normally highest.

With proximal tubular dysfunction, wasting of bicarbonate, phosphate, glucose, and amino acids can be seen. In GSD I, proximal tubular dysfunction has been ascribed to glycogen accumulation in proximal tubular cells or inability to produce glucose for metabolic needs.

In children with poorly controlled GSD I, there tends to be more documentation of aminoaciduria and phosphaturia because these children have such low serum glucose and bicarbonate levels that little tubular reabsorption is required.

The other proximal tubular defects improve with effective therapy such as the provision of CS and, as a result, tend not to be seen in most patients receiving treatment to maintain glucose levels. Along the proximal tubule, there is also sodium-linked reabsorption of calcium and the organic acids such as citrate that can freely cross the glomerular filtration barrier.

The citrate that remains in the urine plays an important role in enhancing the ionic strength of the urine, essentially chelating urinary calcium and helping to prevent its precipitation and the development of nephrolithiasis or nephrocalcinosis.

As a result, individuals with low urinary citrate levels are more predisposed to urinary tract calcifications, and such urinary tract calcifications can increase the chances of urinary tract infection or mediate renal parenchymal damage with loss of renal functional reserve.

With GSD I, instead of the usual increasing urinary excretion of citrate with ongoing maturity, there is an actual decrease in citrate excretion that accelerates during adolescence and early adulthood.

Glycogen deposition in the proximal tubule does reduce proximal tubular calcium reabsorption and is the likely mechanism for altered urinary calcium levels in GSD I.

Hypercalciuria is widespread in prepubertal children with GSD I, and the likelihood for nephrolithiasis and nephrocalcinosis increases with ongoing significant elevation in urinary calcium levels.

Oral citrate supplementation will augment citrate excretion, favorably altering the urinary milieu to decrease the chances of urinary calcium precipitation and, as a result, is likely very beneficial in GSD I patients with low urinary citrate levels Box 4.

In individuals with normal renal function, potassium citrate is preferred over sodium citrate because higher sodium intake is linked to greater urinary calcium excretion. It also can result in systemic hypertension. In older children and adults, potassium citrate tablets at a dose of 10 mEq three times per day can also be commenced and the dose adjusted as needed.

Because the effects of citrate supplementation wane over time, multiple daily doses spread over the waking hours are preferred to maximize the proportion of the day with improved urinary citrate levels.

Citrate use should be monitored because it can cause hypertension and life-threatening hyperkalemia in the setting of renal impairment. Patients should also be monitored for sodium levels. With hypercalciuria, thiazide diuretics can also be provided as a way to enhance renal reabsorption of filtered calcium and decrease urinary calcium excretion.

Especially in GSD I individuals with known urinary tract calcification and ongoing hypercalciuria, thiazide diuretic therapy can be considered.

Chlorothiazide is used in young children who require liquid preparations; tablets of hydrochlorothiazide are recommended for older children and adults. The efficacy of therapy can be gauged by interval urinary calcium-to-creatinine ratios.

This ability to decrease urinary calcium excretion is unique to thiazide diuretics, unlike other classes of diuretics that tend to increase urinary calcium excretion. Other nonspecific measures to reduce urinary calcium deposition, such as optimizing hydration, maintaining a no-added salt diet, or supplementing magnesium intake, can also be considered on an individual basis as well.

GSD I mediates hemodynamic and structural changes in the kidney that can lead to the development of glomerular injury. The exact mechanisms by which these changes occur are not well understood, but activation of the renin—angiotensin system, prolonged oxidative stress, and profibrotic cytokines such as transforming growth factor-β have all been implicated, as well as alterations in renal tubular epithelial cell energy stores related to G6Pase defects.

These changes in GFR may not be readily detected because they result in serum creatinine levels that are often reported as normal. With hyperfiltration, enhanced glomerular blood flow and intraglomerular pressure occur. As glomeruli become obsolete, fibrosis replaces surface area that previously allowed filtration.

Histologically, this injury appears as focal and segmental sclerosis, with a subset of glomeruli demonstrating limited scarring. As more and more glomeruli are lost to scarring, the overall GFR decreases and there is then an accelerated rate of obsolescence in these remnant glomeruli, creating even more stimuli for further glomerular injury.

Over time, microalbuminuria has a tendency to progress to frank proteinuria with urinary protein-to-creatinine ratios exceeding 0.

Chronic proteinuria is thought to exacerbate glomerular injury through induction of chemokines and inflammatory pathways. In GSD I, the development of pathologic proteinuria may be inevitable. In GSD I, this initial period of hyperfiltration that leads to microalbuminuria and frank proteinuria does seem to then progress to widespread glomerular scarring and eventual renal dysfunction.

Most renal biopsy samples from GSD I patients with frank proteinuria or any decrease in GFR demonstrate focal and segmental sclerosis as the histologic change that precedes the loss of renal function and progression to end-stage renal disease.

There have been some data to suggest that metabolic control in GSD I may affect the progression of renal injury. For many years, angiotensin blockade has been used to blunt proteinuria and slow loss of GFR in patients with renal diseases such as diabetes mellitus, in which there is similar hyperfiltration injury.

In cases in which there is a need for further angiotensin blockade, use of both an ACE and an ARB can prove synergistic to reduce proteinuria, with no increased rate of hyperkalemia or drug-related renal insufficiency. Although not yet tested in any systematic fashion in GSD I, the role of initiating angiotensin blockade with the early onset of persistent microalbuminuria seems to be a potential strategy to try to slow the factors that cause accelerated glomerular obsolescence and that ultimately lead to microalbuminuria, proteinuria, and renal insufficiency.

Typical measures to maintain GSD metabolic control are beneficial to general renal health because they help prevent acidosis and limit hyperuricemia and hyperlipidemia.

Chronic acidosis can predispose to higher urinary calcium excretion and decreased urinary citrate, both problems that already exist in GSD I. Hyperuricemia and hyperlipidemia by themselves have both been implicated in causing or accelerating renal injury.

In patients receiving effective dietary therapy for their GSD I, it is unlikely that there will be diffuse proximal tubular dysfunction. There should be periodic assessment of serum electrolytes, calcium, and phosphate as well as interval measurement of blood urea nitrogen and creatinine levels.

GFR should be estimated from the serum creatinine using a validated formula such as the Bedside Schwartz Equation in children or the Modification of Diet in Renal Disease Equation for adults. Screening urinalysis should be performed at intervals on all GSD I patients.

The presence of hematuria determined by dipstick should lead to assessment of urinary calcium excretion and ultrasound imaging of the urinary tract for calcifications.

Even in the absence of hematuria, renal ultrasound should be performed at intervals to assess kidney size and to assess for evolving nephrocalcinosis or nephrolithiasis.

Especially for purposes of screening or for routine follow-up, ultrasound is preferred to other imaging techniques. Despite good metabolic control, hypocitraturia and hypercalciuria may be common in GSD I and, as a result, urine should be assessed at regular intervals for calcium and citrate excretion even if urinalysis is benign.

Spot samples are adequate and easier and quicker to collect than are those of timed urine collection. With hypocitraturia, citrate supplementation should be considered, especially if there is concomitant hypercalciuria or a history of nephrolithiasis or nephrocalcinosis.

With hypercalciuria, there needs to be ongoing good hydration and consideration of thiazide therapy to reduce urinary calcium levels, especially in individuals with known or recurrent urinary tract calcifications.

Urine should also be assessed for microalbuminuria and proteinuria. With a negative screening urinalysis for proteins, urine albuminuria should be quantified by spot albumin-to-creatinine ratio.

Dipstick-positive proteinuria should be quantified by urinary protein-to-creatinine ratio. Positive results should be confirmed using a first morning void sample to rule out any orthostatic component.

Persistent microalbuminuria or frank proteinuria warrants initiation of angiotensin blockade despite patients being normotensive. Medications should be adjusted to try to blunt the proteinuria to levels that are normal or as near normal as possible as tolerated without causing postural hypotension or hyperkalemia.

Attempts should be made to maintain angiotensin blockade chronically, and medication sequelae should be treated in some fashion so that the angiotensin blockade can be maintained or a different type of angiotensin blockade ACE vs.

ARB should be attempted. Because chronic hypertension accelerates renal injury, blood pressure should be maintained in a normal range for adults and at less than the 90th percentile for age, gender, and height for children.

If antihypertensive therapy needs to be started, angiotensin blockade with ACE or ARB should be considered as first-line therapy if not already instituted for other reasons. Loop diuretics should be avoided because of the risk of hypercalciuria. With renal insufficiency, there is decreased production of erythropoietin EPO by the kidney and anemia may develop.

Concomitant clinical factors in GSD patients such as chronic metabolic acidosis, iron deficiency, and bleeding diathesis may potentiate or exacerbate this anemia. In children and adolescents with chronic kidney disease, anemia is linked to impairments in cognitive and developmental gains as well as increased hospitalization rates.

With adults, there are fewer data to support a specific hemoglobin level under which EPO should be started. As a result, EPO therapy is initiated if there is any evolving symptomatic anemia to prevent the need for blood transfusion.

Because iron deficiency anemia is common in GSD I, it is prudent to screen both children and adults with chronic renal failure for iron deficiency anemia and replace iron as needed before starting EPO therapy.

Long-term exposure to nephrotoxic medications should also be avoided. This includes use of nonsteroidal anti-inflammatory drugs such as ibuprofen and is especially important if there is any reduction in GFR or if patients have a bleeding diathesis.

Metabolic derangements from ongoing chronic renal insufficiency may exacerbate some of the issues that arise from GSD, making renal transplantation a more attractive therapy.

In this case the option of both liver and kidney transplant may be considered. Hematologic aspects in GSD I include risk for anemia, bleeding diathesis, and neutropenia in GSD Ib. Anemia is a significant long-term morbidity in individuals with GSD I.

In , Talente et al. The report was based on an observational study of 32 subjects. Anemia in the pediatric population was recognized in ref. The cause of anemia in GSD I is multifactorial—the restricted nature of the diet, chronic lactic acidosis, renal involvement, bleeding diathesis, chronic nature of the illness, suboptimal metabolic control, 40 hepatic adenomas, 29 and irritable bowel disease in GSD Ib are all contributing factors.

In one study it was noted that patients with hemoglobin concentrations 2 SDs below the mean for their age had higher mean daily lactate concentrations as compared with the nonanemic population 3.

An association between severe anemia and large hepatic adenomas was identified as well. Many patients with GSD I have iron deficiency anemia. In some, it is an iron refractory anemia attributable to aberrant expression of hepcidin. It is secreted in the bloodstream and is the key regulator of iron in the body, controlling iron absorption across the enterocyte, as well as macrophage recycling of iron.

In the presence of hepatic adenomas, there are increased hepcidin levels. The inability of hepcidin to be downregulated in the setting of anemia causes abnormal iron absorption and iron deficiency. Intravenous iron infusions can partially overcome the resistance to iron therapy, but, because of an inhibition of macrophage recycling of iron, a good response is typically not seen.

The restricted nature of the diet, with a focus on maintaining normoglycemia, often results in nutritional deficiencies see Nutrition section including poor intake of iron, vitamin B12, and folic acid.

Progression of kidney disease is another risk factor for anemia, and some patients require supplementation with EPO to maintain hemoglobin levels. The causes of anemia in GSD Ib are similar to those of anemia in GSD Ia, as was noted in five subjects studied by Talente et al.

Numerous case reports documented the presence of anemia in this population, but studies of the pathophysiology of this complication were lacking. Interleukin 6—a marker of inflammation known to upregulate hepcidin expression, which is increased during inflammatory bowel disease exacerbations—is the likely cause of low hemoglobin concentrations and another cause for the anemia observed in patients with GSD Ib.

A larger study involving subjects with GSD I at two large GSD centers has shed more light on the causes of anemia in GSD I. Mild anemia is common in the pediatric population because of iron deficiency and dietary restrictions. As previously stated, overall, pediatric patients with anemia have worse metabolic control, but the anemia is responsive to improved therapy and iron supplementation.

By contrast, anemia in adulthood is associated with hepatic adenoma formation, particularly in people with more severe anemia. The finding that all subjects who had resection of the dominant hepatic adenoma experienced resolution of their anemia supports the proposed pathophysiology of hepcidin-induced anemia.

In contrast to the GSD Ia population, there was no association between anemia and metabolic control or hepatic adenomas in either children or adults with GSD Ib; however, a strong association with systemic inflammation was documented.

In GSD I, a coagulation defect attributed to acquired platelet dysfunction with prolonged bleeding times, decreased platelet adhesiveness, and abnormal aggregation has been described Box 5. Bleeding manifestations include epistaxis, easy bruising, menorrhagia, 45 and excessive bleeding during surgical procedures.

Although dietary intervention can ameliorate the bleeding diathesis, the exact etiology of the bleeding diathesis remains unclear. More than one study, with limited numbers of patients, showed that infusions of glucose and total parenteral nutrition corrected the bleeding time and in vitro platelet function in patients with GSD I, suggesting that coagulation defects were secondary to metabolic abnormalities.

These agents could be utilized in patients with GSD I when clinically indicated, but use of deamino d -arginine vasopressin in GSD I must be performed with caution because of the risk of fluid overload and hyponatremia in the setting of i.

glucose administration. In addition, the use of a fibrinolytic inhibitor, such as ɛ-aminocaproic acid Amicar , can be used as an adjunctive medication if there is mucosal-associated bleeding. For more severe mucosal-associated bleeding, an i. If the i. The use of Amicar is contraindicated in individuals with disseminated intravascular coagulation and if activated prothrombin complex concentrate FEIBA has been used.

Caution must be taken to ensure that there is no genitourinary tract bleeding, because inhibition of fibrinolysis can lead to an obstructive nephropathy.

Neutropenia and recurrent infections are common manifestations of GSD Ib. Neutropenia persists throughout childhood with little change in the neutrophil levels.

It is unclear if neutrophil function is normal in this setting. Adult patients also have severe neutropenia and recurrent infections. The patterns of infections vary from patient to patient, but there is no clear genotype—phenotype relationship.

Neutropenia and the susceptibility to infections are now attributed to specific abnormalities in neutrophil production and function. Mutations in glucose 6-phosphate transporter G6PT cause apoptosis of developing neutrophils, ineffective neutrophil production, and neutropenia.

Monocyte functions are also abnormal, probably contributing to the formation of granulomas and chronic inflammatory responses. It is also important to note that some patients with GSD Ia have also been known to develop neutropenia. Individuals with GSD Ia who are homozygous for the mutation p.

GlyArg were reported to have a GSD Ib—like phenotype with neutropenia. G-CSF has been used for treating neutropenia and preventing infections in patients with GSD Ib since refs. This cytokine stimulates and accelerates neutrophil production by the bone marrow, releases neutrophils from the bone marrow, prolongs the survival of the cells, and enhances their metabolic burst.

Administration of G-CSF increases blood neutrophil counts to normal or above normal levels, usually within a few hours. In a review of 18 European patients given either glycosylated or nonglycosylated G-CSF median age: 8 years; treated for up to 7 years , there was a positive clinical response both in the severity of infections and in the manifestations of inflammatory bowel disease in all patients.

Almost all reports on GSD Ib indicate that G-CSF increases blood neutrophil levels, decreases the occurrence of fevers and infections, and improves enterocolitis.

Before G-CSF treatment, median ANC for this group was 0. Treatment can be performed daily, on alternate days, or on a Monday—Wednesday—Friday schedule with similar benefits DC Dale, personal communication , but some children require daily therapy to avoid infections.

G-CSF should be administered subcutaneously starting at 1. The G-CSF dose should be increased in a stepwise manner at approximately 2-week intervals until the target ANC of more than to up to 1. The ANC for these patients is not pushed to higher levels because G-CSF appears to increase the spleen size in GSD Ib patients.

Blood count should be monitored several times per year. The lowest effective G-CSF dose should be used to avoid splenomegaly, hypersplenism, hepatomegaly, and bone pain. With use of G-CSF, occurrences of infections were greatly reduced and inflammatory bowel disease also improved in most, but not all, patients.

In more than patient-years of observations, the Severe Chronic Neutropenia International Registry has recorded three deaths in GSD Ib patients, sepsis, 1; after liver and hematopoietic transplant, 1; hepatomegaly and neutropenia, 1. Side effects of treatment with G-CSF in the GSD Ib population were reported by the European Study on Glycogen Storage Disease Type I.

This complication did regress with reduced treatment. There are known cases in which the splenomegaly did not improve with reduction of the dose and splenectomy was required.

Increase in spleen size and the need to reduce G-CSF dose can usually be determined by physical examination and confirmed by ultrasound when necessary. In addition, this group reported two patients that have been on G-CSF and developed acute myelogenous leukemia. Based on available data, the risk of acute myelogenous leukemia is very low.

However, all patients should be observed, with serial blood counts monitored approximately quarterly for development of loss of response to G-CSF, presence of myeloblasts in the blood, evidence of hypersplenism, new patterns of bone pain, or any other changes that might suggest a change in hematological disease or development of a myeloid malignancy.

In contrast to the hypertrophic cardiomyopathy of GSD II Pompe disease or GSD III, the heart itself is not primarily affected by GSD I. The most common cardiovascular abnormality in patients with GSD I is systemic hypertension Box 6.

This is reviewed in the Nephrology section of this article. There are conflicting data about this question, and two small series examining clinical surrogates of early atherosclerosis found no evidence to suggest early atherosclerosis.

One of the most ominous, yet rare, potential complications of GSD I is the occurrence of pulmonary arterial hypertension PAH. PAH may coexist with numerous systemic illnesses such as rheumatologic diseases, portal hypertension, infections such as HIV , and exposure to toxins anorexigens. PAH is also known to be a complication of several other conditions, such as hypoxic lung disease, thromboembolic disease, pulmonary venous hypertension secondary to left-sided heart disease, and congenital heart disease with left-to-right shunting through the lungs.

Finally, it may occur in isolation as primary PAH. To date, nine GSD I patients with PAH have been reported.

Thank you glycogfn visiting Diagnlsis. You are using a browser version Diagnosis of glycogen storage disease limited support for CSS. To atorage the Diagnksis experience, glycogdn recommend or use a more up to Satiety and energy levels browser or Carbohydrate loading for team sports off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Disclaimer: This guideline is designed primarily as an educational resource for clinicians to help them provide quality medical services. Adherence to this guideline is completely voluntary and does not necessarily ensure a successful medical outcome. This guideline should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. Searching for just a few words Satiety and energy levels sforage enough to get started. If Citrus supplement for healthy skin Satiety and energy levels to Dizgnosis more Diiagnosis queries, use the tips dizease to guide you. The Diagnosis of glycogen storage disease storage diseases GSDs are a group of Diaggnosis metabolic disorders that result from a defect in any one glycoge several enzymes required for either glycogen synthesis or glycogen degradation. The GSDs can be divided into those with hepatic involvement, which present as hypoglycemia, and those which are associated with neuromuscular disease and weakness. The severity of the GSDs range from those that are fatal in infancy if untreated to mild disorders with a normal lifespan. The diagnosis, treatment, and prognosis for the common types of GSDs are reviewed. Broadly speaking, the GSDs can be divided into those with hepatic involvement, which present as hypoglycemia, and those which are associated with neuromuscular disease and weakness Table 1 [ 1 ].