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. Frequent feedings of uncooked cornstarch are used to maintain and improve blood levels of glucose.

Allopurinol, a drug capable of reducing the level of uric acid in the blood, may be useful to control the symptoms of gout-like arthritis during the adolescent years.

Human granulocyte colony stimulating factor GCSF may be used to treat recurrent infections in GSD type Ib patients. Liver tumors adenomas can be treated with minor surgery or a procedure in which adenomas are ablated using heat and current radiofrequency ablation. Individuals with GSDI should be monitored at least annually with kidney and liver ultrasound and routine blood work specifically used for monitoring GSD patients.

Information on current clinical trials is posted on the Internet at www. All studies receiving U. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the National Institutes of Health NIH in Bethesda, MD, contact the NIH Patient Recruitment Office:. Tollfree: TTY: Email: prpl cc. For information about clinical trials sponsored by private sources, contact: www. 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. 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. This suggests that the GSD I patient with a coexisting condition that may also predispose a patient to development of PAH is at the highest risk for this complication.

In all the cases of GSD I with PAH described in the literature, the diagnosis of PAH was not made until it was quite advanced, and in seven of nine patients PAH led to their deaths. Recently, oral medications for PAH, such as sildenafil, have been shown to be effective treatments.

GSD I patients with this serious complication have a better chance of longer survival if PAH is diagnosed at an earlier stage and medical treatment is initiated promptly. Management recommendations for cardiovascular manifestations of GSD I include screening to detect systemic or pulmonary hypertension at early stages when these conditions are most amenable to treatment.

Because systemic hypertension in children is only rarely associated with clinical symptoms such as headaches or vision changes beginning in infancy, accurate measurements of systemic blood pressure should be obtained at all clinic visits.

Any elevated blood pressure measurements should be carefully followed up to confirm the diagnosis of hypertension. It is important to note that age-appropriate and gender-appropriate norms for blood pressure should be applied when reporting it.

Good metabolic control is the best management option for maintaining serum lipid levels as close to normal as possible, thereby reducing the risk of acute pancreatitis and long-term development of atherosclerosis. Management of hyperlipidemia with medications usually does not begin until the patient is at least 10 years old.

Screening for pulmonary hypertension by periodic echocardiography with attention to estimating right-ventricular pressure by tricuspid regurgitation jet is indicated because PAH is unlikely to have clinical features that would be apparent on physical examination or with simple testing such as electrocardiogram until the PAH is well advanced.

Obtaining the tricuspid regurgitation jet by echocardiogram is the best method to periodically screen for elevated right-side heart pressures. Because most of the patients with PAH also had poor metabolic control, achieving good metabolic control may prevent PAH. If PAH is detected, pursuing effective treatment methods such as treatment with Bosentan and Sildenafil in consultation with a physician experienced in managing PAH is recommended.

The primary-care physician should take care of the regular physical examinations and immunizations, as well as any intercurrent medical problem not related to the GSD. Other available immunizations, such as those for seasonal influenza, hepatitis B, and pneumococcal infections polyvalent after 2 years of age , should be offered because they can prevent the hypoglycemia caused by the gastrointestinal manifestations associated with the disease processes.

Hepatitis C status should be monitored in patients at risk. Because patients with GSD I may receive several medications, it is always recommended to check for potential interactions with the physician or pharmacy when a new medication is prescribed.

Drugs that can potentially cause hypoglycemia should be avoided. These include β-blockers, quinidine, sulfonamides Bactrim , pentamidine, and haloperidol, as well as some over-the-counter medications. Antidepressant agents should be used with caution because they can affect glucose regulation hypoglycemia or hyperglycemia.

Insulin and insulin secretagogues sulfonylureas should be used with caution. The use of growth hormone should clearly be limited to only those who are proven to have a growth hormone deficiency and, in this situation, close monitoring for liver adenomas and metabolic disturbances is critical.

The use of aspirin, nonsteroidal anti-inflammatory drugs, and other medications that reduce or affect platelet function should be avoided. Hypoglycemia risks should be checked before starting medications.

Due consideration should be given to medications that have a high sodium or potassium content; the latter is especially important in the setting of renal failure.

All patients should be encouraged to participate in age-appropriate physical activities. However, contact or competitive sports should be avoided because of the risk of liver injury, unless proper protection is used.

Patients should avoid alcohol intake as it may predispose them to hypoglycemia. Good hygiene and frequent hand-washing precautions are advised, especially for patients with neutropenia.

As a general rule, patients should avoid unnecessary contact with sick people, especially during the winter season. Good dental hygiene and frequent monitoring of dental health are advised for all patients, but it is particularly important in patients with GSD Ib, who have a tendency to develop chronic gingivitis.

During intercurrent illnesses, early evaluation and treatment are encouraged to prevent complications, especially when infectious processes are suspected in patients with neutropenia. In such cases more frequent monitoring of BG and additional doses of CS may be indicated.

glucose treatment. The emergency letter should be reviewed annually and updated as needed. Patients should wear a medical alert identification. A variety of types are offered by pharmacies and websites:.

Necklaces and bracelets with engraved patient name, diagnosis, and emergency contact information. org offers a sponsored membership program that provides bracelets with an engraved toll-free telephone number and patient ID number.

Metabolic derangement caused by fasting and infections are a common cause of morbidity in patients with GSD I, even with current treatments. In addition, some illnesses causing anorexia and vomiting interrupt oral or nasogastric feedings.

Patients and their parents should be educated regarding the symptoms of hypoglycemia and metabolic decompensation.

They should be taught to respond to minor ailments by giving frequent oral or NG glucose-containing fluids, and they should be educated regarding the need for emergency care if oral feeds are not tolerated. Of course, due consideration of fluid volume is given in the setting of renal failure.

Intravenous solutions containing lactate are contraindicated and should be avoided. Patients with GSD I cannot tolerate typical periods of fasting before procedures. Progressive metabolic acidosis and cardiac dysrhythmia leading to cardiac arrest during surgery have been reported.

Recommendations have been published as a guide for perioperative management. supply of glucose can be provided.

The i. BG, electrolyte, and lactic acid levels should be monitored. Although administration of dextrose-containing fluids at lower rates can result in normalization of BG, higher doses of glucose are needed to keep the patient anabolic and prevent lactic acidosis. fluids should continue until oral feeding is re-established.

Once the patient is taking oral feedings, the dextrose infusion should be slowly weaned over several hours. Caution should be used when prescribing hormonal birth control; estrogen is known to contribute to development of both benign and malignant hepatocellular tumors Box 9.

Females with GSD I are known to have polycystic ovaries from a young age. Menorrhagia appears to be a problem in females of reproductive age with GSD I.

Management of females with GSD I should include a multidisciplinary approach including the expertise of a gynecologist familiar with GSD I. With significant strides in management of GSD I, patients are surviving into adulthood and pregnancies are now becoming common.

Successful pregnancies have been documented in women with GSD types Ia and Ib. Ideally, it is prudent to plan the pregnancy ahead of time so that metabolic parameters may be monitored and normalized in preparation for pregnancy.

A prepregnancy consultation should be conducted during which adherence to a safe diet routine to avoid low BG, accompanied by frequent BG monitoring, should be emphasized.

Medications such as ACE inhibitors, allopurinol, and lipid-lowering drugs must be discontinued because they are known to cause fetal anomalies.

A baseline ultrasound of the kidneys and liver to monitor for hepatic adenomas should be performed before the patient becomes pregnant. Laboratory tests such as a lipid profile, serum uric acid test, liver function test, complete blood count, and urine protein test should be performed.

Good metabolic control will help normalize most of these parameters if abnormal. In addition, in patients with GSD Ib, conception at a time when inflammatory bowel disease is quiescent may make flare-ups during pregnancy less likely. The high estrogenic state in pregnancy has been reported to cause an increase in adenoma formation.

Increased proteinuria may be noted. Risk of stone formation is typically higher in GSD Ia than in GSD Ib, 40 but renal calcification was noted in two of three pregnant patients with GSD Ib in one case series. Neutropenia and Crohn disease—like enterocolitis are problems unique to GSD Ib.

Low neutrophil counts can lead to infectious complications. G-CSF is classified by the US Food and Drug Administration as a pregnancy class C drug. There are no recommendations for G-CSF use during pregnancy. There are published reports in the literature of normal pregnancy outcomes after G-CSF use.

Management of Crohn disease—like enterocolitis can be problematic in pregnancy because most medications used for treatment are not approved for use during pregnancy. The risk to the fetus from active enterocolitis has to be considered in comparison with the risk from the medications themselves during decision making regarding management.

BG levels should be monitored throughout the process to maintain euglycemia. Transient hypoglycemia has been observed in some neonates. Neonates have been noted to have normal growth and development. There is no contraindication to breastfeeding. Increased metabolic demands will occur while breastfeeding.

It has been observed that not all mothers may be successful at breastfeeding. The website provides descriptions of the various types of GSD and a listserv, a mechanism for people with all forms of GSD to connect via the Internet.

The association also holds a medical conference each year for individuals with GSD and their families. Similar to that for other inborn errors of metabolism, genetic counseling should be offered to all parents of children with GSD I and to adults affected with the condition Box GSD I is an autosomal recessive condition.

De novo mutation rates are expected to be infrequent, and parents of an affected individual are assumed to be carriers. DNA mutation analysis is necessary for the identification of additional family members in the extended family who may be carriers.

Targeted mutation analysis based on ethnic background is available for both the G6PC and SLC37A4 genes. Generally, full sequence analysis is recommended, starting with GSD Ia and then GSD Ib, if clinical suspicion is present. Large deletions and duplications cannot be detected by sequence analysis.

Identification of carrier status in the general population is limited and not routinely offered; however, mutation analysis to further refine the risk of having a child with GSD I can be offered to those at risk e. Prenatal diagnostic testing is typically performed by mutation analysis either on cultured chorionic villus samples or on amniocytes, ideally of the probands of previously identified mutations.

When the mutations segregating in the family are known, molecular testing is the gold standard. Prenatal genetic diagnosis is also an option for families with GSD I if the mutations have been identified. Acute and chronic complications occur in GSD Ia despite adherence to dietary therapy, including growth retardation, hepatomegaly, intermittent hypoglycemia, lactic acidemia, hyperlipidemia, gout related to hyperuricemia, proteinuria, nephrolithiasis, and progressive nephropathy.

Modified CS shows promise for improving dietary therapy because a single dose at bedtime prevented hypoglycemia more effectively throughout the night in comparison with uncooked CS. Perhaps one of the most concerning complications of GSD I is the frequent occurrence of hepatic adenomas in adult patients, which are accompanied by a significant risk for malignant transformation to HCC.

The mechanism for tumorigenesis remains to be elucidated in GSD Ia, although it could include chronic inflammation. Progressive nephropathy is associated with proteinuria in adult patients.

The overexpression of angiotensinogen suggests that suppression of the renin—angiotensin system might be effective in GSD Ia. Microalbuminuria has been effectively treated with low doses of ACE inhibitors such as captopril and lisinopril. In a study of 95 patients with GSD I, a significant and progressive decrease of glomerular hyperfiltration was noted in patients treated with ACE inhibitors.

Hyperlipidemia in GSD Ia can be managed with lipid-lowering drugs such as 3-hydroxymethyl-glutaryl-CoA reductase inhibitors and fibrates. The potential benefit of 3-hydroxymethyl-glutaryl-CoA reductase inhibitors was emphasized by a study that showed increased triglyceride synthesis in GSD Ia patients compared with normal controls.

Hyperuricemia in GSD I can improve with good metabolic control; however, in some situations, hyperuricemia persists and can result in gouty attacks, gouty tophi, and kidney stones.

Use of agents, such as Allopurinol and Febuxostat, have been used to lower uric acid levels. Newer agents, such as pegloticase, have been used in situations where the use of other agents has failed.

Colchicine has been used with success in the acute setting of gouty attacks. At this time, there is no consensus as when to treat hyperuricemia with medications. The development of new therapy for GSD Ia, such as gene therapy or cell therapy, might prevent long-term complications that arise due to recurrent hypoglycemia and related biochemical abnormalities.

Pilot studies of hepatocyte transplantation have demonstrated persistence of donor cells, although the long-term efficacy of this approach remains to be demonstrated , Efficacy from liver-targeted gene therapy in GSD Ia might be expected, given the experience with human patients after liver transplantation.

Furthermore, complications of GSD Ib were incompletely reversed in experiments with an AAV vector encoding G6PT, and longer-term surviving mice developed hepatocellular carcinoma related to inadequate correction. The duration of efficacy from AAV vectors has been limited, because the AAV vector genomes remain largely episomal and are lost after cell division.

A double-stranded AAV vector transduced the liver and kidneys with higher efficiency when pseudotyped as AAV9 rather than the AAV8 vector used for initial experiments; however, G6Pase expression from these vectors gradually waned between 7 and 12 months of age.

The loss of G6Pase could be countered by readministration of an AAV vector of a new serotype to avoid antibodies formed in response to the initial AAV vector treatment. Despite these apparent limitations of gene therapy in GSD I, the development of AAV vector—mediated gene therapy will continue based on the success of early-stage clinical trials of gene therapy in hemophilia.

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Platelet dysfunction in glycogen storage disease type I. Blood ; 41 — Mühlhausen C, Schneppenheim R, Budde U, et al. Decreased plasma concentration of von Willebrand factor antigen VWF:Ag in patients with glycogen storage disease type Ia.

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Renal function and kidney size in glycogen storage disease type I. Pediatr Nephrol ; 6 — Weinstein DA, Somers MJ, Wolfsdorf JI. Decreased urinary citrate excretion in type 1a glycogen storage disease. Marega A, Fregonese C, Tulissi P, et al. Preemptive liver-kidney transplantation in von Gierke disease: a case report.

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Ischemic stroke in an adult with glycogen storage disease type I. J Clin Neurosci ; 17 — Visser G, Rake JP, Labrune P, et al. Consensus guidelines for management of glycogen storage disease type 1b - European Study on Glycogen Storage Disease Type 1.

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Weinstein DA, Somers MJ, Wolfsdorf JI Decreased urinary citrate excretion in type 1a glycogen storage disease. Wolfsdorf JI, Crigler JF Cornstarch regimens for nocturnal treatment of young adults with type I glycogen storage disease. Am J Clin Nutr — Wolfsdorf JI, Crigler JF Effect of continuous glucose therapy begun in infancy on the long-term clinical course of patients with type I glycogen storage disease.

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Wolfsdorf JI, Laffel LM, Crigler JF Metabolic control and renal dysfunction in type I glycogen storage disease. Download references. Glycogen is the form of sugar your body stores in your liver and muscles for future energy needs. Glycogen storage diseases are complex genetic conditions in which certain enzymes -- ones involved in creating glycogen or breaking it down into sugar for your body to use -- are missing or don't work correctly.

This can result in liver, heart, muscle, and respiratory problems. While there is no cure, our team of internationally recognized experts uses special diets and medical treatments to manage these diseases and their symptoms. We work you or your child to improve growth, development, and health.

Our physical and occupational therapists and speech pathologists may also work with you to develop muscle strength and improve other weaknesses. We work with your primary care doctor throughout the year so you or your child can receive care close to home.

Typically, people come to Duke once to twice a year for follow-up with our specialists. Living with glycogen storage disease means closely monitoring lab test results, as well as regular tests and screening to diagnose complications when they arise. Severe forms of glycogen storage disease can damage the heart and lungs and cause infections.

We work closely with your hometown doctors to follow our treatment plan and so that tests can be performed closer to home. The effects of some forms of glycogen storage disease can be reversed by maintaining healthy levels of vitamins, minerals, and enzymes for proper growth and development.

Sometimes a feeding tube is recommended for continuous feeding. People with glycogen storage disorders often work with physical and occupational therapists to build strength and promote proper development. These therapies can help you or your child with motor skills for tasks of daily living.

Weakened muscles and developmental delays related to glycogen storage disorders can impact speech. Our speech pathologists use speech therapy to teach children how to make the correct mouth movements to improve their spoken words and language acquisition.

Surgery may be necessary if the liver, heart, or digestive tract is affected by the disease. If serious damage occurs, organ transplants may be recommended. We use family history and medical tests to diagnose glycogen storage diseases.

Treatments vary for the various types of GSD. Glycogen storage disease type I GSD I , also known as von Gierke disease, accounts for about 25 percent of all children with GSD.

Symptoms typically appear when an infant is 3 to 4 months of age and may include hypoglycemia low blood sugar , which can cause fatigue , constant hunger, and crankiness. 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.

The effects of some forms of glycogen storage disease can be reversed by maintaining healthy levels of vitamins, minerals, and enzymes for proper growth and development. Sometimes a feeding tube is recommended for continuous feeding.

People with glycogen storage disorders often work with physical and occupational therapists to build strength and promote proper development. These therapies can help you or your child with motor skills for tasks of daily living. Weakened muscles and developmental delays related to glycogen storage disorders can impact speech.

Our speech pathologists use speech therapy to teach children how to make the correct mouth movements to improve their spoken words and language acquisition.

Surgery may be necessary if the liver, heart, or digestive tract is affected by the disease. If serious damage occurs, organ transplants may be recommended. We use family history and medical tests to diagnose glycogen storage diseases. Prenatal testing is also available. The following tests may be ordered.

May be used to monitor the health of the liver, kidneys, and muscles, and ensure proper blood sugar levels. Can uncover the presence of disease-causing genetic changes. It is used to check for certain disease markers and hereditary traits.

Tissue samples taken from the liver and muscle are studied to look for disease or abnormal cell function. Contrast-enhanced ultrasound, CT, and MRI create detailed pictures of the size, structure, and function of organs and vessels. This nonsurgical alternative to a liver biopsy uses ultrasound to check for liver stiffness from scarring, called liver fibrosis.

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Find a Glycogen Storage Diseases Doctor. Close Doctor Overlay. Search Doctors by Condition, Specialty or Keyword Clear Search Text. Filter Results. Filter Results Close Filters of Doctor Search.

Located Near. Located Near You Remove User Location. Distance Distance 5 miles 10 miles 25 miles 50 miles Clear filter. 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. This suggests that the GSD I patient with a coexisting condition that may also predispose a patient to development of PAH is at the highest risk for this complication.

In all the cases of GSD I with PAH described in the literature, the diagnosis of PAH was not made until it was quite advanced, and in seven of nine patients PAH led to their deaths. Recently, oral medications for PAH, such as sildenafil, have been shown to be effective treatments. GSD I patients with this serious complication have a better chance of longer survival if PAH is diagnosed at an earlier stage and medical treatment is initiated promptly.

Management recommendations for cardiovascular manifestations of GSD I include screening to detect systemic or pulmonary hypertension at early stages when these conditions are most amenable to treatment.

Because systemic hypertension in children is only rarely associated with clinical symptoms such as headaches or vision changes beginning in infancy, accurate measurements of systemic blood pressure should be obtained at all clinic visits.

Any elevated blood pressure measurements should be carefully followed up to confirm the diagnosis of hypertension. It is important to note that age-appropriate and gender-appropriate norms for blood pressure should be applied when reporting it. Good metabolic control is the best management option for maintaining serum lipid levels as close to normal as possible, thereby reducing the risk of acute pancreatitis and long-term development of atherosclerosis.

Management of hyperlipidemia with medications usually does not begin until the patient is at least 10 years old. Screening for pulmonary hypertension by periodic echocardiography with attention to estimating right-ventricular pressure by tricuspid regurgitation jet is indicated because PAH is unlikely to have clinical features that would be apparent on physical examination or with simple testing such as electrocardiogram until the PAH is well advanced.

Obtaining the tricuspid regurgitation jet by echocardiogram is the best method to periodically screen for elevated right-side heart pressures. Because most of the patients with PAH also had poor metabolic control, achieving good metabolic control may prevent PAH.

If PAH is detected, pursuing effective treatment methods such as treatment with Bosentan and Sildenafil in consultation with a physician experienced in managing PAH is recommended. The primary-care physician should take care of the regular physical examinations and immunizations, as well as any intercurrent medical problem not related to the GSD.

Other available immunizations, such as those for seasonal influenza, hepatitis B, and pneumococcal infections polyvalent after 2 years of age , should be offered because they can prevent the hypoglycemia caused by the gastrointestinal manifestations associated with the disease processes.

Hepatitis C status should be monitored in patients at risk. Because patients with GSD I may receive several medications, it is always recommended to check for potential interactions with the physician or pharmacy when a new medication is prescribed.

Drugs that can potentially cause hypoglycemia should be avoided. These include β-blockers, quinidine, sulfonamides Bactrim , pentamidine, and haloperidol, as well as some over-the-counter medications.

Antidepressant agents should be used with caution because they can affect glucose regulation hypoglycemia or hyperglycemia. Insulin and insulin secretagogues sulfonylureas should be used with caution. The use of growth hormone should clearly be limited to only those who are proven to have a growth hormone deficiency and, in this situation, close monitoring for liver adenomas and metabolic disturbances is critical.

The use of aspirin, nonsteroidal anti-inflammatory drugs, and other medications that reduce or affect platelet function should be avoided. Hypoglycemia risks should be checked before starting medications.

Due consideration should be given to medications that have a high sodium or potassium content; the latter is especially important in the setting of renal failure.

All patients should be encouraged to participate in age-appropriate physical activities. However, contact or competitive sports should be avoided because of the risk of liver injury, unless proper protection is used.

Patients should avoid alcohol intake as it may predispose them to hypoglycemia. Good hygiene and frequent hand-washing precautions are advised, especially for patients with neutropenia.

As a general rule, patients should avoid unnecessary contact with sick people, especially during the winter season. Good dental hygiene and frequent monitoring of dental health are advised for all patients, but it is particularly important in patients with GSD Ib, who have a tendency to develop chronic gingivitis.

During intercurrent illnesses, early evaluation and treatment are encouraged to prevent complications, especially when infectious processes are suspected in patients with neutropenia. In such cases more frequent monitoring of BG and additional doses of CS may be indicated.

glucose treatment. The emergency letter should be reviewed annually and updated as needed. Patients should wear a medical alert identification.

A variety of types are offered by pharmacies and websites:. Necklaces and bracelets with engraved patient name, diagnosis, and emergency contact information. org offers a sponsored membership program that provides bracelets with an engraved toll-free telephone number and patient ID number.

Metabolic derangement caused by fasting and infections are a common cause of morbidity in patients with GSD I, even with current treatments. In addition, some illnesses causing anorexia and vomiting interrupt oral or nasogastric feedings. Patients and their parents should be educated regarding the symptoms of hypoglycemia and metabolic decompensation.

They should be taught to respond to minor ailments by giving frequent oral or NG glucose-containing fluids, and they should be educated regarding the need for emergency care if oral feeds are not tolerated. Of course, due consideration of fluid volume is given in the setting of renal failure.

Intravenous solutions containing lactate are contraindicated and should be avoided. Patients with GSD I cannot tolerate typical periods of fasting before procedures. Progressive metabolic acidosis and cardiac dysrhythmia leading to cardiac arrest during surgery have been reported.

Recommendations have been published as a guide for perioperative management. supply of glucose can be provided. The i. BG, electrolyte, and lactic acid levels should be monitored.

Although administration of dextrose-containing fluids at lower rates can result in normalization of BG, higher doses of glucose are needed to keep the patient anabolic and prevent lactic acidosis. fluids should continue until oral feeding is re-established.

Once the patient is taking oral feedings, the dextrose infusion should be slowly weaned over several hours. Caution should be used when prescribing hormonal birth control; estrogen is known to contribute to development of both benign and malignant hepatocellular tumors Box 9.

Females with GSD I are known to have polycystic ovaries from a young age. Menorrhagia appears to be a problem in females of reproductive age with GSD I. Management of females with GSD I should include a multidisciplinary approach including the expertise of a gynecologist familiar with GSD I.

With significant strides in management of GSD I, patients are surviving into adulthood and pregnancies are now becoming common. Successful pregnancies have been documented in women with GSD types Ia and Ib. Ideally, it is prudent to plan the pregnancy ahead of time so that metabolic parameters may be monitored and normalized in preparation for pregnancy.

A prepregnancy consultation should be conducted during which adherence to a safe diet routine to avoid low BG, accompanied by frequent BG monitoring, should be emphasized. Medications such as ACE inhibitors, allopurinol, and lipid-lowering drugs must be discontinued because they are known to cause fetal anomalies.

A baseline ultrasound of the kidneys and liver to monitor for hepatic adenomas should be performed before the patient becomes pregnant. Laboratory tests such as a lipid profile, serum uric acid test, liver function test, complete blood count, and urine protein test should be performed.

Good metabolic control will help normalize most of these parameters if abnormal. In addition, in patients with GSD Ib, conception at a time when inflammatory bowel disease is quiescent may make flare-ups during pregnancy less likely.

The high estrogenic state in pregnancy has been reported to cause an increase in adenoma formation. Increased proteinuria may be noted. Risk of stone formation is typically higher in GSD Ia than in GSD Ib, 40 but renal calcification was noted in two of three pregnant patients with GSD Ib in one case series.

Neutropenia and Crohn disease—like enterocolitis are problems unique to GSD Ib. Low neutrophil counts can lead to infectious complications.

G-CSF is classified by the US Food and Drug Administration as a pregnancy class C drug. There are no recommendations for G-CSF use during pregnancy.

There are published reports in the literature of normal pregnancy outcomes after G-CSF use. Management of Crohn disease—like enterocolitis can be problematic in pregnancy because most medications used for treatment are not approved for use during pregnancy.

The risk to the fetus from active enterocolitis has to be considered in comparison with the risk from the medications themselves during decision making regarding management. BG levels should be monitored throughout the process to maintain euglycemia.

Transient hypoglycemia has been observed in some neonates. Neonates have been noted to have normal growth and development. There is no contraindication to breastfeeding. Increased metabolic demands will occur while breastfeeding. It has been observed that not all mothers may be successful at breastfeeding.

The website provides descriptions of the various types of GSD and a listserv, a mechanism for people with all forms of GSD to connect via the Internet. The association also holds a medical conference each year for individuals with GSD and their families.

Similar to that for other inborn errors of metabolism, genetic counseling should be offered to all parents of children with GSD I and to adults affected with the condition Box GSD I is an autosomal recessive condition. De novo mutation rates are expected to be infrequent, and parents of an affected individual are assumed to be carriers.

DNA mutation analysis is necessary for the identification of additional family members in the extended family who may be carriers.

Targeted mutation analysis based on ethnic background is available for both the G6PC and SLC37A4 genes. Generally, full sequence analysis is recommended, starting with GSD Ia and then GSD Ib, if clinical suspicion is present. Large deletions and duplications cannot be detected by sequence analysis.

Identification of carrier status in the general population is limited and not routinely offered; however, mutation analysis to further refine the risk of having a child with GSD I can be offered to those at risk e.

Prenatal diagnostic testing is typically performed by mutation analysis either on cultured chorionic villus samples or on amniocytes, ideally of the probands of previously identified mutations.

When the mutations segregating in the family are known, molecular testing is the gold standard. Prenatal genetic diagnosis is also an option for families with GSD I if the mutations have been identified.

Acute and chronic complications occur in GSD Ia despite adherence to dietary therapy, including growth retardation, hepatomegaly, intermittent hypoglycemia, lactic acidemia, hyperlipidemia, gout related to hyperuricemia, proteinuria, nephrolithiasis, and progressive nephropathy.

Modified CS shows promise for improving dietary therapy because a single dose at bedtime prevented hypoglycemia more effectively throughout the night in comparison with uncooked CS. Perhaps one of the most concerning complications of GSD I is the frequent occurrence of hepatic adenomas in adult patients, which are accompanied by a significant risk for malignant transformation to HCC.

The mechanism for tumorigenesis remains to be elucidated in GSD Ia, although it could include chronic inflammation. Progressive nephropathy is associated with proteinuria in adult patients.

The overexpression of angiotensinogen suggests that suppression of the renin—angiotensin system might be effective in GSD Ia. Microalbuminuria has been effectively treated with low doses of ACE inhibitors such as captopril and lisinopril.

In a study of 95 patients with GSD I, a significant and progressive decrease of glomerular hyperfiltration was noted in patients treated with ACE inhibitors.

Hyperlipidemia in GSD Ia can be managed with lipid-lowering drugs such as 3-hydroxymethyl-glutaryl-CoA reductase inhibitors and fibrates. The potential benefit of 3-hydroxymethyl-glutaryl-CoA reductase inhibitors was emphasized by a study that showed increased triglyceride synthesis in GSD Ia patients compared with normal controls.

Hyperuricemia in GSD I can improve with good metabolic control; however, in some situations, hyperuricemia persists and can result in gouty attacks, gouty tophi, and kidney stones.

Use of agents, such as Allopurinol and Febuxostat, have been used to lower uric acid levels. Newer agents, such as pegloticase, have been used in situations where the use of other agents has failed.

Colchicine has been used with success in the acute setting of gouty attacks. At this time, there is no consensus as when to treat hyperuricemia with medications.

The development of new therapy for GSD Ia, such as gene therapy or cell therapy, might prevent long-term complications that arise due to recurrent hypoglycemia and related biochemical abnormalities. Pilot studies of hepatocyte transplantation have demonstrated persistence of donor cells, although the long-term efficacy of this approach remains to be demonstrated , Efficacy from liver-targeted gene therapy in GSD Ia might be expected, given the experience with human patients after liver transplantation.

Furthermore, complications of GSD Ib were incompletely reversed in experiments with an AAV vector encoding G6PT, and longer-term surviving mice developed hepatocellular carcinoma related to inadequate correction. The duration of efficacy from AAV vectors has been limited, because the AAV vector genomes remain largely episomal and are lost after cell division.

A double-stranded AAV vector transduced the liver and kidneys with higher efficiency when pseudotyped as AAV9 rather than the AAV8 vector used for initial experiments; however, G6Pase expression from these vectors gradually waned between 7 and 12 months of age.

The loss of G6Pase could be countered by readministration of an AAV vector of a new serotype to avoid antibodies formed in response to the initial AAV vector treatment.

Despite these apparent limitations of gene therapy in GSD I, the development of AAV vector—mediated gene therapy will continue based on the success of early-stage clinical trials of gene therapy in hemophilia.

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