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.

• Splenomegaly

  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. [symptoma.com]

  Some potential complications associated with Andersen's Disease include: Scarring of the liver; liver cirrhosis Liver failure Development of an enlarged spleen (splenomegaly), which reduces the number of blood cells in the body This can result in anemia [dovemed.com]

  Ultrasound revealed a small, cirrhotic liver, portal vein thrombosis, and splenomegaly. After sclerotherapy ascites developed and diuretics were administered with good result. [adc.bmj.com]

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

  Most of these patients develop portal hypertension and the following associated complications of portosystemic blood shunting: Esophageal varices Encephalopathy Splenomegaly Renal dysfunction Hepatic functional capacity also progressively declines, including [emedicine.medscape.com]

• Failure to Thrive

  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. [symptoma.com]

  Such signs typically include failure to thrive – slow growth and failure to gain weight at the expected rate. There may be an abnormally large liver and spleen. [agsd.org.uk]

  Symptoms of GSD 4 usually begin in infancy and typically include failure to thrive; enlarged liver and spleen (hepatosplenomegaly); and in many cases, progressive liver cirrhosis and liver failure. [diseaseinfosearch.org]

  The first indication of a problem is a failure to thrive. The rate of growth and mental progress of the baby stops at a certain point and does not continue normally. [agsdus.org]

  Symptoms of GSD 4 usually begin in infancy and typically include failure to thrive ; enlarged liver and spleen ( hepatosplenomegaly ); and in many cases, progressive liver cirrhosis and liver failure. [rarediseases.info.nih.gov]

• Vomiting

  (type 7) exertional fatigue in childhood, nausea, vomiting, muscle cramps/weakness, hyperuricemia (d/t inc. degradation of muscle purine nucleotides), arthritis (d/t hyperuricemia), myoglobinuria, or frank anuria following high-intensity exerciseTarui [memorize.com]

  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]

  […] disease Myopathy Hypoglycemia Hyperlipidemia DGUOK Deoxyguanosine kinase deficiency AR Severe hypotonia Liver disease Nystagmus Lactic acidosis Developmental regression MPV17 MPV17-related mtDNA maintenance defect AR Liver disease Hepatomegaly Hypotonia Vomiting [ncbi.nlm.nih.gov]

  The symptoms are due to hypoglycemia and include lethargy, pallor, nausea, vomiting, and sometimes seizures in the morning before breakfast. [wjgnet.com]

• Nausea

  (type 7) exertional fatigue in childhood, nausea, vomiting, muscle cramps/weakness, hyperuricemia (d/t inc. degradation of muscle purine nucleotides), arthritis (d/t hyperuricemia), myoglobinuria, or frank anuria following high-intensity exerciseTarui [memorize.com]

  The symptoms are due to hypoglycemia and include lethargy, pallor, nausea, vomiting, and sometimes seizures in the morning before breakfast. [wjgnet.com]

• Heart Failure

  Milder forms have been reported with later-onset, marked by muscular weakness or cardiomyopathy and heart failure. [orpha.net]

  Complications with these forms may include heart failure. [rarediseases.info.nih.gov]

  Patients with cardiomyopathy often develop progressive heart failure, which may lead to death despite medical and surgical intervention. [emedicine.medscape.com]

  In severe cases, muscle weakness and heart problems develop In severe cases, infants may suffer heart failure by the age of 18 months Milder forms of type II may not cause heart problems Type III - Cori's Disease Swollen abdomen due to an enlarged liver [chp.edu]

• 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]

  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]

  Prognosis is good; adult patients have normal stature and minimal hepatomegaly. [ommbid.mhmedical.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]

• Hepatosplenomegaly

  Case report A 16 month old boy presented with hepatosplenomegaly and hypotonia. 8 The combination of hepatosplenomegaly, disturbed muscle function, and the histological finding of cirrhosis and glycogen storage in the liver led to a diagnosis of GSD IV [adc.bmj.com]

  The disease was seen in a patient exhibiting progressive hepatosplenomegaly along with the storage of an abnormal glycogen that had poor solubility in the liver. [themedicalbiochemistrypage.org]

  aseptic necrosis of femur, bone crises, macrophages that look like crumpled tissue paperGauchers disease deficient in sphingomyelinaseniemann-Pick disease accumulation of sphingomyelinniemann-Pick disease progressive neurodegeneration, hepatosplenomegaly [memorize.com]

  Symptoms of GSD 4 usually begin in infancy and typically include failure to thrive; enlarged liver and spleen (hepatosplenomegaly); and in many cases, progressive liver cirrhosis and liver failure. [diseaseinfosearch.org]

  Symptoms of GSD 4 usually begin in infancy and typically include failure to thrive ; enlarged liver and spleen ( hepatosplenomegaly ); and in many cases, progressive liver cirrhosis and liver failure. [rarediseases.info.nih.gov]

• Muscle Cramp

  Not bad Glycogen Storage Disease Type VII (Tarui Disease) Muscle PFK deficiency Similar to McArdle's but more severe Findings: 1) Exercise intolerance 2) Muscle cramps * RBCs show some % of normal activity Mnemonic for Glycogen Storage Diseases Violins [quizlet.com]

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

  (type 7) exertional fatigue in childhood, nausea, vomiting, muscle cramps/weakness, hyperuricemia (d/t inc. degradation of muscle purine nucleotides), arthritis (d/t hyperuricemia), myoglobinuria, or frank anuria following high-intensity exerciseTarui [memorize.com]

  In some types of this disease, children must limit their amount of exercise to reduce muscle cramps. Some GSD types cannot be treated, while others are fairly easy to control by treating the symptoms. [cincinnatichildrens.org]

  The predominant clinical features of glycogen storage diseases that mainly affect the muscle are muscle cramps, exercise intolerance, susceptibility to fatigue, and progressive weakness. [ommbid.mhmedical.com]

• Myalgia

  The main complaints are exercise‐induced myalgia and fatigue. [cochranelibrary.com]

  Patients may report progressive muscle weakness, myalgia, and lack of endurance since childhood or adolescence[ 161 ]. [wjgnet.com]

• Muscle Hypotonia

  Clinical features are muscle hypotonia and cirrhosis. Death from liver disease usually occurs before age 2. [icd10data.com]

• Severe Short Stature

  Clinical features : hepatomegaly, glucose and galactose intolerance, fasting hypoglycaemia, proximal tubular nephropathy and severe short stature. Symptoms persist into adulthood. Treatment : there is no specific therapy available. [patient.info]

• Neonatal Hypotonia

  Neonatal hypotonia and cardiomyopathy secondary to type IV glycogenosis. Acta Neuropathol (Berl). 1994;87:531-36. Starzl TE, et al. Chimerism after liver transplantation for type IV glycogen storage disease and type 1 Gaucher’s disease. [rarediseases.org]

  This form is characterized by polyhydramnios, neonatal hypotonia, and neuronal involvement; hepatopathy is uncommon, and the babies usually die between 4 weeks and 4 months of age. [humpath.com]

  Neonatal hypotonia and cardiomyopathy secondary to type IV glycogenosis. Acta Neuropathol 1994; 87 : 531–536. 12. Nambu M, Kawabe K, Fukuda T, Okuno TB, Ohta S, Nonaka I et al. A neonatal form of glycogen storage disease type IV. [nature.com]

  Profound neonatal hypotonia at birth, respiratory failure, dilated cardiomyopathy, early infantile death Classic (progressive) hepatic subtype. [ncbi.nlm.nih.gov]

• Hyporeflexia

  In congenital form, the patients have severe hypotonia, hyporeflexia, cardiomyopathy, depressed respiration and neuronal involvement[ 104, 112 - 114 ]. Liver involvement is not severe and the child dies in early infancy. [wjgnet.com]

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.

• Hypoglycemia

  […] 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) 1) Hepato/renalmegaly 2) Fasting hypoglycemia [quizlet.com]

  Hypoglycemia and hyperlipidemia are variable and, if present, usually mild. There is no hyperlactic acidemia or hyperuricemia. Treatment is based on the symptoms with a high-carbohydrate diet and frequent feedings to alleviate hypoglycemia. [ommbid.mhmedical.com]

  (type 7) deficient enzyme is glucose 6 phosphataseVon Gierkes findings include severe fasting hypoglycemia (d/t Glc stuck in liver), inc blood lactate, hepatomegaly (d/t inc glycogen in liver), hyperlipidemia (d/t hypoglycemia --> inc glucagon --> inc [memorize.com]

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

  The clinical picture changes from mild to moderate hypoglycemia. Despite gross hepatomegaly patient is largely asymptomatic without hypoglycemia. [wjgnet.com]

• Hyperuricemia

  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) 1) Hepato/renalmegaly 2) Fasting hypoglycemia - SEVERE 3) Lactic acidemia 4) Hyperuricemia [quizlet.com]

  (type 7) exertional fatigue in childhood, nausea, vomiting, muscle cramps/weakness, hyperuricemia (d/t inc. degradation of muscle purine nucleotides), arthritis (d/t hyperuricemia), myoglobinuria, or frank anuria following high-intensity exerciseTarui [memorize.com]

  The clinical manifestations are growth retardation, hepatomegaly, hypoglycemia, lactic acidemia, hyperuricemia, and hyperlipidemia. [ommbid.mhmedical.com]

  A cause of hypotonia, hyperuricemia, and growth retardation". Am J Dis Child. 139 (6): 609–13. PMID 3859203. ↑ Hendrickx J, Coucke P, Hors-Cayla MC, Smit GP, Shin YS, Deutsch J; et al. (1994). [wikidoc.org]

  Allopurinol (10 mg/kg per day, divided into 3 dosages) should be given if hyperuricemia is present. [wjgnet.com]

• 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 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.

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.

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.

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

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.

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.

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.

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.

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.