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Glycogen Storage Disease Type 3

Cori Disease

Glycogen storage disease type III, also known as Cori's disease, Forbes disease or limit dextrinosis, is characterized by deficiency of the cytosolic debrancher enzyme.


Presentation

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]
  • 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]
  • 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]
  • 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]
Exertional Chest Pain
  • A 32-year-old man was referred with exertional chest pain. He had been diagnosed with glycogen storage disease type IIIa (GSDIIIa) by liver biopsy in childhood.[circ.ahajournals.org]
Hepatomegaly
  • 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]
  • 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]
  • 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]
  • 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]
Withdrawn
  • When diet was withdrawn in one of the patients he complained of chest pain, reduced physical strength and creatine kinase levels rapidly increased. This was reversed when Atkins diet was reintroduced.[ojrd.biomedcentral.com]

Workup

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].

Albuminuria
  • (iii) Albuminuria, aminoaciduria. Mellituria : This is a condition in which sugars are excreted in urine. Glycogen Storage Diseases: Type # 7. Lactosuria : Lactosuria occurs in women during the period of lactation.[biologydiscussion.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]
  • 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]
  • Both defects lead to inadequate hepatic conversion of glucose-6-phosphate to glucose through normal glycogenolysis and gluconeogenesis, making affected individuals susceptible to fasting hypoglycemia not responsive to glucagon infusion (2) .[journals.lww.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]
  • Hers' disease has a mild course with risk of growth retardation, mild fasting hypoglycemia, and delayed motor development in early childhood.[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]

Treatment

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

Prognosis

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].

Etiology

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.

Epidemiology

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.

Sex distribution
Age distribution

Pathophysiology

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].

Prevention

There are no guidelines for prevention of GSD Type III.

Summary

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.

Patient Information

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.

References

Article

  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

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Last updated: 2018-06-21 18:40