Edit concept Create issue ticket

Glycogen Storage Disease Type 4

Andersen Disease

Glycogen storage disease type IV, also known as Glycogen branching enzyme deficiency, Andersen's disease or amylopectinosis is a rare inherited metabolic disorder.


Presentation

Clinically there are many variations in presentation. As soon as the disease begins, there is accumulation of the long un-branched chains mainly in the liver tissues causing hepatomegaly. This leads to derangement in the normal functioning of the liver. Cirrhosis may be further seen as a consequence of continued metabolic disorder. Jaundice is visible and progressive in nature. Splenomegaly is seen in most of the individuals.

Rarely does the disease affect the peripheral nerves; when it does, neuromuscular symptoms are evident. It leads to hypotonia, gait disturbances and lumbar lordosis. Waddling gait causes difficulty in walking. Hepatic failure ensues and hence, there is failure to thrive seen in infants.
Cardiac manifestations like cardiomegaly might be seen in few individuals.

Sputum
  • Some signs and symptoms associated with Andersen's Disease include: Breathing difficulties Productive cough with bloody sputum Variations in skin tone and color Weakness and exhaustion; inability to perform physical activities Decreased muscle mass Neuromuscular[dovemed.com]
Productive Cough
  • Some signs and symptoms associated with Andersen's Disease include: Breathing difficulties Productive cough with bloody sputum Variations in skin tone and color Weakness and exhaustion; inability to perform physical activities Decreased muscle mass Neuromuscular[dovemed.com]
Hepatomegaly
  • As soon as the disease begins, there is accumulation of the long un-branched chains mainly in the liver tissues causing hepatomegaly. This leads to derangement in the normal functioning of the liver.[symptoma.com]
  • In the non-progressive hepatic type, hepatomegaly and liver disease are usually evident in early childhood, but affected individuals typically do not develop cirrhosis.[ghr.nlm.nih.gov]
  • In addition, assay for branching enzyme deficiency in muscle, leukocytes, erythrocytes, or fibroblasts can be carried out to determine the exact defect resulting in the hepatomegaly.[themedicalbiochemistrypage.org]
  • Glycogen Disease of the Liver Leads to hepatomegaly Types: 1, 3, 4, 6 Glycogen Disease of the Muscle Exercise intolerance and muscle weakness Types: 5 and 7 Glycogen storage disease Type Ia (von Gierke Disease) G-6-Pase deficiency Findings: (same as Ib[quizlet.com]
  • Clinical symptoms in IXa include hepatomegaly, growth restriction, hyperlipidaemia and fasting ketosis.[patient.info]
Muscle Hypotonia
  • Clinical features are muscle hypotonia and cirrhosis. Death from liver disease usually occurs before age 2.[icd10data.com]

Workup

  1. A Complete blood count will show anemia and neutropenia.
  2. Blood glucose levels will depict a picture of hypoglycemia as there is excess of glycogen circulating in the body but poor amount of usable glucose.
  3. Liver function tests are altered due to hepatomegaly and cirrhosis of liver.
  4. Serum creatinine kinase levels tend to be elevated. This is the most important test done in all patients suspected of Glycogen storage diseases.
  5. Coagulation studies will be abnormal due to altered liver function. There will be increased tendency to bleed in patients. Altered prothrombin time will be seen.
  6. Lipid studies will show hyperlipidemia.
  7. Renal function tests might be done. Serum creatinine might be elevated.
  8. Urine tests will reveal myoglobinuria.
  9. Direct biochemical assay of tissues for glycogen and fat content will give a definitive diagnosis.
  10. Enzyme analysis of GBE1 will also confirm the diagnosis as it is a very sensitive test.

Imaging

Hepatomegaly will be seen on Ultra Sonography.
Echocardiography will reveal the cardiac involvement in individuals.

Ischemic forearm test is done in all cases of muscle disorders and is an important diagnostic tool.

Genetic diagnosis [7]

GBE1 deficiency leads to the disorder. Biochemical genetic testing can be done by testing GBE1 activity. Placental involvement [8] is also seen.

Glucose Decreased
  • These signs and symptoms include reduced blood glucose, decreased muscle mass, weakness, enlarged liver and spleen, and even heart abnormalities.[dovemed.com]

Treatment

Treatment of Glycogen storage disease type 4 is only palliative and not curative. There is no complete cure as it is an inherited disorder. Patients can be given appropriate diet to reduce hepatomegaly and cirrhosis and complications can be delayed. Care must be taken to give foods which will help in improving weight of the child. Deficiencies of certain fat soluble vitamins are very important as they are not absorbed in case of hepatic function alteration. Vitamin and protein supplements can take care of these nutritional deficits.

Cardiac consultation and neurological testing are extremely useful as it will help to evaluate disease prognosis.
Liver transplantation [9] is the treatment of choice for hepatic failure in such patients.

Prognosis

The infants who are affected congenitally or in the womb itself will have a bad prognosis as they cannot survive more than few months and die of hepatic failure and failure to thrive. Hypotonia will lead to disability in those who survive and hence there will be a tendency to dependency on others for life.

The milder forms like neuromuscular type have a comparatively better prognosis. Morbidity is chiefly due to hepatosplenomegaly, hepatic failure and failure to thrive seen in affected individuals.

Etiology

Deficient activity of glycogen branching enzyme is the cause of Glycogen storage disease type 4. It is considered as a hereditary metabolic disorder. Andersen’s disease is an autosomal recessive disease.

There are many neuromuscular variants of this disease depending on the onset of origin. It may be evident at birth, in late childhood or adulthood.

The peri-natal variant shows symptoms usually few months after birth and is fatal to the growth of the infant.
Mutations in the GBE1 gene give rise to Glycogen storage disease type 4. The GBE1 gives instructions for the production of the glycogen branching enzyme. This enzyme is involved in the production of glycogen which is the major source of energy stored in the body.

Epidemiology

Glycogen storage diseases in general are very few, around 2 per 1,00,000 children. Glycogen storage disease type 4 is rarer.

Sex distribution
Age distribution

Pathophysiology

Glycogen branching enzyme [2] is deficient in all the tissues of the body in Glycogen storage disease type 4. This leads to formation of extremely long chains of glycogen which normally would be branched had the enzyme been present. The long un-branched chains have a very low solubility and get deposited in the liver. These long chains get stored in the other bodily tissues producing symptoms fatal to the neonate.

The accumulated glycogen is abnormal in structure and impairs the functioning of the organs where it gets deposited. There are 5 subtypes of Glycogen storage disease type 4 based on the severity, signs and symptoms.

The fatal perinatal neuromuscular type [3] is the most severe form of disease. The symptoms develop before birth itself. Symptoms like excess fluid accumulation around the fetus and in the body of the fetus are seen. Fetal akinesia develops which may cause decreased movements of the fetus in utero. There is arthrogryposis (joint stiffness) and deformities seen. There will be hypotonia and muscular atrophy noticed in the infant after birth. These infants will not survive post neonatal period due to a weakened heart [4] and altered breathing muscles.
The congenital muscular type of Glycogen storage disease type 4 is noticed in infants just a few months after birth. Affected infants have high grade of hypotonia which affects all the muscles of breathing. There will be weakening of the heart muscles and dilated cardiomyopathy [5] ensues.

The progressive hepatic type [6] of is the most common type of Glycogen storage disease type 4. There will be failure to thrive in infants as there is difficulty in gaining weight and associated hepatomegaly. High blood pressure in the portal veins will lead to portal hypertension and soon ascites develops. These children generally die of hepatic failure.

The non- progressive hepatic type of Glycogen storage disease type 4 has the same features like the hepatic variant but the hepatic dysfunction is less severe. There is hypotonia and myopathy noticed in these individuals.

The childhood neuromuscular type of disease is a late onset disorder and the children suffer from muscle weakness and cardiomyopathy.

Prevention

Prenatal diagnosis must be established and is a very important step towards prevention of complications. Molecular genetic testing can be evaluated by analysis of DNA extracted from fetal cells. Genetic counseling is a very useful tool as it is an inherited disorder and the progeny will have 25% to 50% chance of being affected. It can be avoided by testing the parents for their carrier status.

Summary

The glycogen storage diseases are enzyme deficiency diseases which are transmitted hereditarily from one generation to another. Certain enzymes are necessary for conversion of glycogen to glucose and the deficiency of one or more of these enzyme leads to excess of glycogen circulating in the body. The enzyme defect will result in consequences that will cause systemic symptoms or in certain cases limited to a few tissues.

The Glycogen storage disease type 4 is also called as Andersen’s disease or Amylopectinosis or Brancher enzyme deficiency or Polyglucosan Body Disease [1]. The disease usually manifests in childhood owing to its inherited origin. There is no cure for this disease but following certain diet therapy, one can modify the clinical symptoms.

Patient Information

Glycogen storage disorder type 4 is one of the variants of the types of storage disorders. It is also called as Anderson’s disease or glycogen brancher enzyme deficiency disease. The main defect is a deficiency of glycogen branching enzyme which results in variations in the glycogen storage. The deficiency of the glycogen branching enzyme results in circulation of long un-branched glycogen chains which are low molecular weight and hence, easily get deposited at various organs.

It commonly affects the liver and abnormal liver function is seen in infants and children especially. If it affects the neonate congenitally it tends to be very fatal as there will be splenomegaly, failure to thrive and distention of abdomen. There is evidence of cardiomyopathy too in these neonates [10]. In infants where there is neuromuscular involvement, hypotonia (decreased muscle tone) is noticed. There is also stiffness of joints in such neonates and thus, there is tendency to deformities of joints. There will be weakening of the heart and difficulty in breathing. Usually neonates suffering from this variety of disease will not survive far beyond birth.

It is an autosomal recessive type of disease and thus, inherited from the parents. There will be a chance that the next offspring may also suffer from the disease. There are many investigations which can confirm the diagnosis. Prenatal diagnosis can also be done by finding out GBE1 deficiency in the tissues or the amniotic fluid. There are significant alterations in the liver function tests and coagulation studies. Creatinine kinase levels are elevated and there will be high myoglobin levels in the urine samples. Ultra-sonography reveals an enlarged liver, ascites and splenomegaly.
Appropriate diet to reduce liver enlargement remains the most palliative form of treatment children can follow. Liver transplantation remains the main stand of treatment and if done below 2 years of age will have excellent prognosis. Regular checkups with the cardiologists and neurologists will help prevent further complications. Genetic counseling will help the parents to decide about the different aspects and difficulties faced in planning the next child.

References

Article

  1. Nolte KW, Janecke AR et al. Congenital type IV glycogenosis: the spectrum of pleomorphic polyglucosan bodies in muscle, nerve, and spinal cord with two novel mutations in the GBE1 gene. Acta Neuropathol. 2008 Nov;116(5):491-506.
  2. Assereto S, van Diggelen OP et al. Null mutations and lethal congenital form of glycogen storage disease type IV. Biochem Biophys Res Commun. 2007 Sep 21;361(2):445-50. Epub 2007 Jul 24.
  3. Escobar LF, Wagner S et al. Neonatal presentation of lethal neuromuscular glycogen storage disease type IV. J Perinatol. 2012 Oct;32(10):810-3.
  4. Lee YC, Chang CJ et al. Glycogen-branching enzyme deficiency leads to abnormal cardiac development: novel insights into glycogen storage disease IV. Hum Mol Genet. 2011 Feb 1;20(3):455-65.
  5. Aksu T, Colak A, Tufekcioglu O et al. Cardiac Involvement in Glycogen Storage Disease Type IV: Two Cases and the Two Ends of a Spectrum. Case Reports in Medicine, vol. 2012, Article ID 764286, 4 pages, 2012.
  6. Lamperti C, Salani S et al. Neuropathological study of skeletal muscle, heart, liver, and brain in a neonatal form of glycogen storage disease type IV associated with a new mutation in GBE1 gene. J Inherit Metab Dis. 2009 Dec;32 Suppl 1:S161-8.
  7. Bruno C, van Diggelen OP et al. Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV). Neurology. 2004 Sep 28;63(6):1053-8.
  8. Konstantinidou AE, Anninos H et al. Placental involvement in glycogen storage disease type IV. Placenta. 2008 Apr;29(4):378-81.
  9. Iyer SG, Chen CL et al. Long-term results of living donor liver transplantation for glycogen storage disorders in children. Liver Transpl. 2007 Jun;13(6):848-52.
  10. Moses SW, Parvari R et al. The variable presentations of glycogen storage disease type IV: a review of clinical, enzymatic and molecular studies. Curr Mol Med. 2002 Mar;2(2):177-88.

Ask Question

5000 Characters left Format the text using: # Heading, **bold**, _italic_. HTML code is not allowed.
By publishing this question you agree to the TOS and Privacy policy.
• Use a precise title for your question.
• Ask a specific question and provide age, sex, symptoms, type and duration of treatment.
• Respect your own and other people's privacy, never post full names or contact information.
• Inappropriate questions will be deleted.
• In urgent cases contact a physician, visit a hospital or call an emergency service!
Last updated: 2018-06-21 18:23