The clinical manifestations are nonmyopathic even though the enzyme is readily seen in all tissues. The patient history is made of infant seizures. Hepatomegaly and growth retardation are other common features.

Muscle weakness progresses very slowly and vigorous exercise is not associated with tenderness, cramping and myoglobulinuria [6]. Cortical malformations are also reported in many cases. Polymicrogyria is rarely reported but is an important symptom.

GSD type 3a is more common and the prognosis is much more unfavorable than GSD type 3b. The major clinical features of GSD type 3a are Cardiomegaly and cardiomyopathy, muscular weakness and atrophy (especially around the limb musculature), hepatomegaly (with or without splenomegaly) and general cardiac and skeletal muscle abnormalities.

GSD type 3b is less common and it is seen roughly 15% of the time. It is more favorable prognostically than GSD type 3a. With GSD type 3a, the liver is the only organ involved.

Hepatosplenomegaly is moderate while mild fibrosis and micronodular cirrhosis of the liver are rare and clinically silent. Hepatomegaly is pronounced during childhood but usually normalizes when the individual gets to puberty [7]. Patients with GSD type 3b reach their expected height as growth is accelerated at puberty.

• Short Stature

  Some individuals have short stature and noncancerous (benign) tumors called adenomas in the liver. [rarediseases.info.nih.gov]

  Reaction catalyzed by glycogen debranching enzyme Deficiency in glycogen debranching activity causes hepatomegaly, ketotic hypoglycemia, hyperlipidemia, variable skeletal myopathy, cardiomyopathy and results in short stature. [themedicalbiochemistrypage.org]

  Some individuals have short stature and noncancerous (benign) tumors called adenomas in the liver. GSDIII is cause by mutations in the AGL gene and is inherited in an autosomal recessive manner. [diseaseinfosearch.org]

  Digital slides Case 34 : glycogen storage disease type 3 (GSD3) Case 46 : glycogen storage disease type 3 (GSD3) Case 247 : glycogen storage disease type 3 (GSD3) Synopsis short stature growth retardation carniofacial anomalies midface hypoplasia deep-set [humpath.com]

  People with GSDIII often have slow growth because of their liver problems, which can lead to short stature. In a small percentage of people with GSDIII, noncancerous (benign) tumors called adenomas may form in the liver. [ghr.nlm.nih.gov]

• Fatigue

  In the early morning the child may have low blood sugar which could cause: Paleness Vomiting Extreme fatigue Convulsions The children may also have a mild growth delay. They also may have poor exercise tolerance. [cancercarewny.com]

  The goal of treatment is to avoid muscle fatigue and/or cramps induced by exercise. [chp.edu]

  Symptoms may range from mild fatigue to temporarily incapacitating fatigue with muscle cramping. Late-onset cases may begin showing symptoms of progressive muscle weakness at 60–70 years of age. [encyclopedia.com]

  Fatigue and muscle cramps after exertion. Mild growth restriction in some cases. Specific biochemical features : Hypoglycaemia, ketosis, raised fasting lactate. [patient.info]

  Clinical features may include hepatomegaly, hypoglycemia, muscle cramps, exercise intolerance, and progressive fatigue and weakness. Preliminary biochemical testing may be helpful in making a diagnosis. [mayomedicallaboratories.com]

• Asymptomatic

  Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. [ncbi.nlm.nih.gov]

  The symptoms of disease in the liver group are similar, ranging from symptomatic hypoglycemia and ketoacidosis to largely asymptomatic enlargement of the liver (hepatomegaly). [britannica.com]

  The discovery of oligosymptomatic and asymptomatic sibs suggested that there are persons with undiagnosed hepatic glycogen synthase deficiency. [sandwalk.blogspot.com]

  Apart from transient asymptomatic hypoglycaemia at the initiation of MAD no serious adverse effects were observed. [ojrd.biomedcentral.com]

  For predictive testing of asymptomatic individuals, it is important to first document the presence of a gene mutation in an affected family member. [mayomedicallaboratories.com]

• Pallor

  Gitzelmann et al. (1996) stated that the disorder should be sought in children who, before the first meal of the day, present with drowsiness, lack of attention, pallor, uncoordinated eye movements, disorientation, or convulsions, and who have hypoglycemia [sandwalk.blogspot.com]

• Failure to Thrive

  […] to thrive, death by 5 years Rare nonprogressive form: no cirrhosis, live to adulthood; adult onset progressive neurogenic bladder, gait difficulties (i.e. spasticity and weakness) from mixed upper and lower motor neuron involvement, sensory loss predominantly [pathologyoutlines.com]

  Clinical features : Hepatomegaly, failure to thrive, cirrhosis, splenomegaly, jaundice, hypotonia, waddling gait, lumbar lordosis. [patient.info]

  This form of glycogen storage disease typically presents in the first year of life, with hepatosplenomegaly and failure to thrive. Hypoglycemia is rarely seen. [ommbid.mhmedical.com]

• Heart Disease

  Heart disease leads to death at about 1.5 years of age. Heredity autosomal recessive Test duration 1-2 weeks after arrival of the sample in the lab Order now! [shop.labogen.com]

  In the infantile form of Pompe's disease, this is the cause of heart disease, respiratory deficiency, and overall muscle weakness. Cori's disease GSD type III is also known as Cori's disease. [encyclopedia.com]

• Hypotension

  These symptoms may exist because individuals with neutropenia often have infection.[3] Children may show signs of irritability and poor feeding.[10] Additionally, hypotension has also been observed in individuals who have this condition.[6] Causes[edit [en.wikipedia.org]

• Hepatomegaly

  Reaction catalyzed by glycogen debranching enzyme Deficiency in glycogen debranching activity causes hepatomegaly, ketotic hypoglycemia, hyperlipidemia, variable skeletal myopathy, cardiomyopathy and results in short stature. [themedicalbiochemistrypage.org]

  Hepatomegaly and growth retardation are other common features. Muscle weakness progresses very slowly and vigorous exercise is not associated with tenderness, cramping and myoglobulinuria. Cortical malformations are also reported in many cases. [symptoma.com]

  Accumulation of glycogen and fat is seen in the liver and kidneys, and is responsible for hepatomegaly and renomegaly. Typically, untreated infants presented at age 3 to 4 months with hepatomegaly, hypoglycemic seizures, or both. [journals.lww.com]

  Clinically, patients with GSD III present in infancy or early childhood with hepatomegaly, hypoglycemia, and growth retardation. [humpath.com]

  Clinical symptoms in IXa include hepatomegaly, growth restriction, hyperlipidaemia and fasting ketosis. [patient.info]

• Renal Insufficiency

  Kidney transplantation can be performed in case of severe renal insufficiency. Combined liver-kidney grafts have been performed in a few cases. [atlasgeneticsoncology.org]

• Kidney Failure

  One half of cases filter blood in the urine after intense exercise, which may be indicative of impending kidney failure. A small percentage of McArdle's cases have seizures. [encyclopedia.com]

• Convulsions

  He had a hypoglycaemic attack which caused generalised convulsions at the age of 3 years. Enzymatic assay showed a deficiency in debranching enzyme activity. [jmg.bmj.com]

  Erythro-cyte glycogen content was 417 mcgm/g Hb (normal value The child was suspected to have glycogen storage disorder based on findings of gradual abdominal distension, history of convulsions, massive hepatomegaly, hypoglycemia, hypertriglyceridemia [indianpediatrics.net]

  In the early morning the child may have low blood sugar which could cause: Paleness Vomiting Extreme fatigue Convulsions The children may also have a mild growth delay. They also may have poor exercise tolerance. [cancercarewny.com]

  Gitzelmann et al. (1996) stated that the disorder should be sought in children who, before the first meal of the day, present with drowsiness, lack of attention, pallor, uncoordinated eye movements, disorientation, or convulsions, and who have hypoglycemia [sandwalk.blogspot.com]

Fasting hypoglycemia and ketonuria may be noted. Hyperlipidemia may be present as well. Elevated Serum aminotransferase and CK levels are normal [8].

Baseline levels of CK do not exclude GSD type 3. In GSD type 3b, serum aminotransferase levels are elevated during childhood but usually normalize at puberty.

Usually, serum lactate and uric acid levels are in the reference range. In GSD type 3, echosonography may be utilized. This noninvasive method that can provide useful information about the size of the liver, spleen, and heart [9].

• Enlargement of the Liver

  The symptoms of disease in the liver group are similar, ranging from symptomatic hypoglycemia and ketoacidosis to largely asymptomatic enlargement of the liver (hepatomegaly). [britannica.com]

  As they get older, children with this condition typically develop an enlarged liver (hepatomegaly). [ghr.nlm.nih.gov]

  Some GSDs affect mostly the liver. These include Types 0, I, III, VI, and IX. These types (except for GSD type 0) may cause the liver to become enlarged. [my.clevelandclinic.org]

• Hypoglycemia

  During periods of hypoglycemia, Cori disease is treated with frequent high carbohydrate meals with cornstarch supplements. A high protein diet is also an effective treatment as this drives gluconeogenesis. [themedicalbiochemistrypage.org]

  Preliminary Laboratory Findings Ketotic hypoglycemia with fasting is a prominent feature of GSD III. However, non-ketotic hypoglycemia has been reported [Seigel et al 2008]. [ncbi.nlm.nih.gov]

  The hypoglycemia inhibits insulin secretion which, in turn, also inhibits protein synthesis and growth is ceased. f. Hypoglycemia stimulates epinephrine production which causes the breakdown of muscle glycogen forming lactate. [biologydiscussion.com]

  Clinically, patients with GSD III present in infancy or early childhood with hepatomegaly, hypoglycemia, and growth retardation. [humpath.com]

  In infancy and early childhood, the disease may be indistinguishable from GSD I because hepatomegaly, hypoglycemia, hyperlipidemia, and growth retardation are common; however, in contrast to GSD I, after puberty, liver size and hypoglycemia usually improve [journals.lww.com]

• Hypertriglyceridemia

  Biological findings include hypoglycemia without acidosis, hypertriglyceridemia, and hypertransaminasemia during childhood. [orpha.net]

  Hypertriglyceridemia and pancreatitis in a patient with apolipoprotein E7 (p.[E244K; E245K])/ E4. Clin Chim Acta, 436: 188-192, 2014. 2013年 Kondo Y, et al. [okiken.tokyo]

  Severe hypertriglyceridemia unresponsive to optimized dietary management may cause acute pancreatitis; lowering triglyceride concentrations with fenofibrate reduces the risk of pancreatitis. [clinicaladvisor.com]

  Erythro-cyte glycogen content was 417 mcgm/g Hb (normal value The child was suspected to have glycogen storage disorder based on findings of gradual abdominal distension, history of convulsions, massive hepatomegaly, hypoglycemia, hypertriglyceridemia [indianpediatrics.net]

  The clinical symptoms include hepatomegaly, growth retardation, elevation of glutamate-pyruvate transaminase and glutamate-oxaloacetate transaminase, hypercholesterolemia, hypertriglyceridemia, and fasting hyperketosis (Schimke et al., 1973; Willems et [sandwalk.blogspot.com]

• Fasting Hypoglycemia

  GSD III is characterized by fasting hypoglycemia, hepatomegaly, growth retardation, progressive myopathy, and cardiomyopathy due to storage of abnormally structured glycogen in both skeletal and cardiac muscles and/or liver. [ncbi.nlm.nih.gov]

  Serum analysis showed mild fasting hypoglycemia (values of 40–45 mg/dL, without increase in glycemia after glucagon load following an overnight fast), hyperlipidemia (triglycerides 251 mg/dL, total cholesterol 268 mg/dL), mild hyperuricemia (5.8 mg/dL [journals.lww.com]

  Fasting hypoglycemia and ketonuria may be noted. Hyperlipidemia may be present as well. Elevated Serum aminotransferase and CK levels are normal. Baseline levels of CK do not exclude GSD type 3. [symptoma.com]

  Differentiating patients with GSD type III from those with GSD type I solely on the basis of physical findings is not easy, but the hepatomegaly, increased liver glycogen content, fasting hypoglycemia, and muscle weakness are consistent with Cori disease [usmle.biochemistryformedics.com]

  In times of fasting, which is essentially any time dietary glucose is not being ingested, severe hypoglycemia can result. [encyclopedia.com]

• Hyperlactacidemia

  Our patient presented with platelet dysfunction, mild hyperlipidemia and hyperuricemia, hyperlactacidemia, and hypoglycemia not responsive to glucagon infusion as characteristics of GSD I. [journals.lww.com]

  Phenotype and clinics Patients have poor tolerance to fasting (with hypoglycemia and hyperlactacidemia after 3 to 4 hours of fasting), marked hepatomegaly, full-cheeked round face, growth retardation (small stature and delayed puberty), generally improved [atlasgeneticsoncology.org]

• Liver Biopsy

  During the follow-up, hypertransaminasemia (2X) persisted, which prompted a repeat liver biopsy; however, the findings were similar to the previous biopsy and the presence of limit dextrin was not noted. [journals.lww.com]

  He had been diagnosed with glycogen storage disease type IIIa (GSDIIIa) by liver biopsy in childhood. Cine cardiovascular magnetic resonance (CMR) demonstrated profound symmetrical hypertrophy (483 g) with impaired systolic function. [circ.ahajournals.org]

  Liver biopsy revealed an increase in the glycogen content (6 percent of wet weight). In which of the following enzymes is a genetic deficiency most likely for this patient? A. Branching enzyme B. Debranching enzyme C. Glucose-6-phosphatase D. [usmle.biochemistryformedics.com]

  A definite diagnosis and sub-typing (determining IIIa versus IIIb type) requires either liver biopsies or DNA based genetic testing. [agsdus.org]

  Second-born of three siblings (the younger also affected), she was suspected with GSD IIIa at 8 months of age (clinical findings of hypoglycemia and hepatomegaly) and the diagnosis was then confirmed by liver biopsy (residual enzymatic activity: 0-zero [air.unimi.it]

• Hepatocellular Carcinoma

  In GSD III, hepatic cirrhosis – not adenomas − leads to hepatocellular carcinoma [Demo et al 2007]. In contrast, in GSD I hepatocellular carcinoma develops in existing adenomas. [ncbi.nlm.nih.gov]

  Prognosis Rarely, patients may develop complications such as hepatic failure or hepatocellular carcinoma. The documents contained in this web site are presented for information purposes only. [orpha.net]

  Complications : include hepatocellular carcinoma, liver failure, heart failure, nerve dysfunction and ventricular arrhythmia. Prognosis : mostly death by age 4, due to cirrhosis and portal hypertension. [patient.info]

  Glycogen storage disease type III-hepatocellular carcinoma a long-term complication?. J Hepatol. 2007 Mar. 46(3):492-8. [Medline]. Kalkan Ucar S, Coker M, et al. [emedicine.medscape.com]

  (REVIEW) PMID 18449899 Hepatocellular carcinoma in glycogen storage disease type Ia: a case series. Franco LM, Krishnamurthy V, Bali D, Weinstein DA, Arn P, Clary B, Boney A, Sullivan J, Frush DP, Chen YT, Kishnani PS. [atlasgeneticsoncology.org]

There is no specific treatment for GSD Type III. If hypoglycemia occurs, the patient should consume frequent high-protein meals.

The prognosis of GSD type III is much better than what is obtainable with GSD type I Many patients with GSD type III survive to adulthood.

GSD type 3b is a milder form of the disease, while in GSD type 3, the prognosis depends a lot on the cardiac system [10].

The GSD type 3 is caused by a deficiency in the debrancher enzyme. The deficit of this enzyme is confined to the liver in GSD type 3b but in GSD type 3a, the deficit can be seen in the skeletal muscles and the myocardium.

With this type of GSD, there is a correlation between the severity of clinical presentation and residual enzyme activity [3]. The debrancher enzyme is coded by a gene mapped to band 1p21. In patients spanning different ethnicities, more than 30 different mutations of the gene have been identified.

The disease is normally inherited as an autosomal recessive trait and prenatal diagnosis and carrier detection are possible by DNA mutation analysis.

Internationally, the incidence and frequency of inherited metabolic conditions place the occurrence of GDs type 3 at 2.3 children per 100,000 live births [2].

The hypoglycemic seizures that occur in the first decade of life may lead to immediate morbidity.

Hepatic disease and progressive muscle weakness are the major causes of long term morbidity.

With an enzyme defect, carbohydrate metabolic pathways get blocked and excess glycogen accumulates in affected tissues. Each GSD represents a specific enzyme defect, and the enzyme is in specific or most of the body tissues.

The enzyme amylo-1,6-glucosidase is deficient and this leads to the accumulation of dextrin. The site of glycogen accumulation is cytoplasmic most of the time. Conversion is usually a one-way reaction from glycogen into glucose-1,6-phosphate [4]. The enzyme is seen in all tissues.

The disease results from a pan-deficiency of the enzyme (GSD 3a) and muscle-specific retention of glycogen debranching enzyme (GSD 3b). The condition is autosomal recessive. No common mutation has been described in Cori disease (types a and b), although 2 alleles have been reported for GSD 3b and 1 allele has been found in North African Jewish people with GSD 3a.

Although the most prevalent mutations have been reported in the North African Jewish population and in an isolate such as the Faroe Islands, 3 novel mutations and 5 known mutations among 22 Tunisian patients with GSD 3 was recorded in the past.

The GSD type 3b arises due to mutation in exon 3 of the glycogen debranching enzyme. Different haplotypes of GSD type 3a have also been recorded. GSD 3 does not only occur in humans. It can equally be found in other mammals [5].

There are no guidelines for prevention of GSD Type III.

Glycogen storage disease type III is an inherited error of metabolism which is characterized by the deficiency in enzymes that debranch glycogen [1]. The condition is an autosomal recessive metabolic disorder.

The GSD type 3 is equally referred to as the Cori disease in honor of the 1947 Nobel laureates Gerty Cori and Carl Cori. Other names for this condition are the limit dextrinosis and the Forbes disease, honoring the American physician Gilbert Burnett Forbes who expanded the features of this disorder even further.

Glycogen is the body’s molecule for storing carbohydrate energy. The symptoms consistent with GSD type 3 are caused when there is a deficiency of the debrancher enzyme or the amylo-1,6 glucosidase. When this is the case, abnormal glycogen gets deposited in the liver, muscles and in some rare cases, heart. The GSD type 3 has two sub types A and B.

Parents need to be fully educated about the genetic implications of this disorder. It is hereditary and thus it runs in families.

Therefore, if anyone you know in your family or one of your children or even you have this defect, the doctor will direct you to a specialist in genes (geneticist). With your full co-operation, this expert will be able to tell you what the chances are for your next child to be diagnosed with this condition.

If as a mother you are already pregnant, it is still possible to have some tests carried out very early into the pregnancy. This will help you to figure out if the unborn child has the GSD Type III or not.

The test is pretty straightforward and involves taking a sample of the amniotic fluid (fluid from around the baby in your womb). With this, the doctor will be able to study the makeup of the enzyme and fully determine if the unborn child has glycogen disorder or not.

If you have a child that has been diagnosed with the disease, you don’t need to panic as the outlook for this condition is positive. Most people with the condition respond well to treatment as long as they are judiciously adhered to. Your doctor will discuss in detail all you need to know regarding treatment.

1. Okubo M, Kanda F, Horinishi A, et al. Glycogen storage disease type IIIa: first report of a causative missense mutation (G1448R) of the glycogen debranching enzyme gene found in a homozygous patient. Hum Mutat. Dec 1999;14(6):542-3.
2. Aoyama Y, Ozer I, Demirkol M, et al. Molecular features of 23 patients with glycogen storage disease type III in Turkey: a novel mutation p.R1147G associated with isolated glucosidase deficiency, along with 9 AGL mutations. J Hum Genet. Nov 2009;54(11):681-6.
3. Cheng A, Zhang M, Okubo M, et al. Distinct mutations in the glycogen debranching enzyme found in glycogen storage disease type III lead to impairment in diverse cellular functions. Hum Mol Genet. Jun 1 2009;18(11):2045-52.
4. Endo Y, Fateen E, El Shabrawy M, et al. Egyptian glycogen storage disease type III - identification of six novel AGL mutations, including a large 1.5 kb deletion and a missense mutation p.L620P with subtype IIId. Clin Chem Lab Med. 2009;47(10):1233-8.
5. Mili A, Ben Charfeddine I, Mamaï O, Abdelhak S, Adala L, Amara A, et al. Molecular and biochemical characterization of Tunisian patients with glycogen storage disease type III. J Hum Genet. Mar 2012;57(3):170-5.
6. Lucchiari S, Fogh I, Prelle A, et al. (2002). "Clinical and genetic variability of glycogen storage disease type IIIa: seven novel AGL gene mutations in the Mediterranean area". Am. J. Med. Genet. 109 (3): 183–90. 
7. The Human Gene Mutation Database at http://www.hgmd.cf.ac.uk/ac/index.php
8. Lei KJ, Chen YT, Chen H, et al. Genetic basis of glycogen storage disease type 1a: prevalent mutations at the glucose-6-phosphatase locus. Am J Hum Genet 1995; 57:766.
9. Akanuma J, Nishigaki T, Fujii K, et al. Glycogen storage disease type Ia: molecular diagnosis of 51 Japanese patients and characterization of splicing mutations by analysis of ectopically transcribed mRNA from lymphoblastoid cells. Am J Med Genet 2000; 91:107.
10. Ekstein J, Rubin BY, Anderson SL, et al. Mutation frequencies for glycogen storage disease Ia in the Ashkenazi Jewish population. Am J Med Genet A 2004; 129A:16