Type IV Glycogen Storage Disease / Andersen Disease - A Detailed Overview

Introduction

Glycogen, a complex sugar, accumulates in the body's cells, leading to the genetic illness known as glycogen storage disease type IV (GSD IV). Certain organs and tissues, especially the liver and muscles, suffer from the structural abnormalities the stored glycogen brings, compromising their function. The other names for this condition are:

• Amylopectinosis.

• Andersen disease.

• Andersen glycogenosis.

• Andersen's disease.

• Brancher deficiency.

• Branching enzyme deficiency.

• Glycogen branching enzyme deficiency.

• Glycogen storage disease IV.

• Glycogen storage disease type 4.

• Glycogenosis 4.

• Glycogenosis, type IV.

• GSD IV.

• GSD type IV.

• GSD4.

What Are the Types and Symptoms of GSD IV?

GSD type IV disease is differentiated into five types depending on the onset and severity of the signs and symptoms. The different types of GSD IV are:

The Fatal Perinatal Neuromuscular Type - It is the most severe form of GSD IV, with symptoms appearing before birth. Due to weak heart and breathing muscles, these infants typically do not survive past the newborn stage.

• Symptoms

  • Polyhydramnios - Too much fluid accumulation around the fetus and inside the fetus’s body.

  • Fetal Akinesia Deformation Sequence - Decreased fetal movements.

  • Arthrogryposis - Joint stiffness after birth.

  • Muscle Atrophy - Muscle wasting.

  • Severe Hypotonia - Abnormally decreased muscle tone.

Congenital Neuromuscular Subtype - Usually not noticeable before birth, begins to manifest in the first few months of life.

• Symptoms

  • Hypotonia - Poor muscle tone.

  • Dilated Cardiomyopathy - Cardiac muscle becomes enlarged and weak.

  • Respiratory Distress - Difficulty in breathing.

The Progressive Hepatic Type - Most common type of GSD IV. Without a liver transplant, liver failure usually results in death by age five.

• Symptoms

  • Failure to Thrive - Affected newborns struggle in the first few months of infancy to acquire weight and develop at the expected rate.

  • Hepatomegaly - Enlarged liver.

  • Liver Cirrhosis - Scarring of the liver.

  • Portal Hypertension - Elevated blood pressure in the vein that supplies the liver.

  • Ascites - Abnormal fluid accumulation in the abdomen.

The Non-progressive Hepatic Type - The liver disease is not as severe in the non-progressive hepatic variant of GSD IV. Still, it shares many of the same characteristics as the progressive type. Hepatomegaly and liver disease become prominent in early childhood in the non-progressive hepatic type but affected people usually do not advance to cirrhosis. They may not exhibit involvement of the heart, skeletal muscles, or nervous system, but they are likely to survive without the liver illness progressing. Although life expectancy varies depending on the severity of the signs and symptoms, most people with this type live into adulthood.

• Symptoms

  • Hypotonia.

  • Myopathy.

The Childhood Neuromuscular Type - This subtype is uncommon, and its course varies, beginning in the second decade with a moderate illness course and ending in death in the third decade or the second decade with a more severe, progressive course. The severity of this kind of GSD IV varies widely; some individuals only experience minor muscle wasting, whereas others develop severe cardiomyopathy and face death in adolescence.

• Symptoms

  • Myopathy - Muscle weakness.

  • Dilated cardiac myopathy.

What Is the Inheritance Pattern of GSD IV?

The inheritance pattern of this disease is an autosomal recessive pattern. The majority of genes are transmitted to all persons in pairs. How an illness is transmitted down through the family depends on how many copies of a gene with a disease-causing variant exist. This illness has an autosomal recessive inheritance pattern. Any chromosome besides the X or Y chromosomes can contain an autosomal gene (sex chromosomes). Genes typically appear in pairs, just like chromosomes. Recessive means that both copies of the illness-causing gene (pathogenic variant) must carry the disease-causing modification for an individual to develop the condition. Mutations is an older term that has been used to describe pathogenic variants. A child with an autosomal recessive disease inherits a gene with a dangerous mutation from each parent. The pathogenic variant of the gene is present in one copy in each parent, making each parent a carrier. Autosomal recessive disease carriers typically do not show any disease symptoms. The pregnancy of two carriers increases the risk of producing a child with an autosomal recessive illness by 25 percent (1 in 4).

What Are the Causes of GSD IV?

GBE1 gene mutations bring on GSD IV. The glycogen branching enzyme is made using instructions from the GBE1 gene. Glycogen, produced by this enzyme, is an essential source of the body's stored energy. The glycogen branching enzyme is in insufficient supply (deficient) due to GBE1 gene mutations that cause GSD IV. Glycogen does not develop properly as a result. Polyglucosan bodies, an abnormal form of glycogen, build up in cells and cause harm and eventual cell death. Throughout the body, polyglucosan bodies build up in cells, but in GSD IV, muscle and liver cells are most severely impacted. The buildup of glycogen in the liver causes hepatomegaly and liver dysfunction. Muscle weakness and atrophy result from muscle cells' inability to use glycogen for energy. The quantity of functional glycogen branching enzyme produced correlates with the condition's severity. Compared to those with the childhood neuromuscular type, people with the fatal perinatal neuromuscular type often produce less than 5 % of usable enzyme and may have up to 20 % of enzyme function. Between 5 and 20 % of the enzyme is typically active in the other kinds of GSD IV. These estimations, however, varied amongst the various categories.

How Is GSD IV Diagnosed?

Based on the clinical signs and the discovery of abnormally branched glycogen buildup in muscle or liver tissue, the diagnosis of glycogen storage disease type IV (GSD IV) is suspected. In addition, biallelic pathogenic mutations in GBE1 or the confirmation of glycogen branching enzyme (GBE) deficiency in liver, muscle, or skin fibroblasts serve to confirm the diagnosis.

• Clinical Findings - The various clinical findings according to the subtypes of GSD IV are

  • Fatal Perinatal Neuromuscular Subtype - Prenatally detectable fetal hydrops, polyhydramnios, and decreased fetal movements; arthrogryposis; severe hypotonia; muscle atrophy at delivery; and early neonatal mortality.

  • Congenital Neuromuscular Subtype - Respiratory failure, dilated cardiomyopathy, severe newborn hypotonia at birth, and early death.

  • Classic Progressive Hepatic Subtype - Hepatomegaly, liver dysfunction, cirrhosis of the liver progressing with ascites, esophageal varices, hypotonia, and cardiomyopathy; death from liver failure usually occurs by the age of five.

  • Non - Progressive Hepatic Subtype - Childhood hypotonia, myopathy, and liver dysfunction.

  • Childhood Neuromuscular Subtype - Chronic, progressive myopathy; some people also have dilated cardiomyopathy.

• Laboratory Findings

  • The hepatic subtypes often have higher liver enzyme levels.

  • Hypoalbuminemia - Decreased plasma - protein (albumin).

  • Prolonged partial thromboplastin time (PTT) and prothrombin time (PT), along with steadily declining liver function.

• Ultrasound Imaging - Usually, an abdominal ultrasound indicates an enlarged liver with cirrhosis or fibrosis symptoms.

• Histopathology - The affected tissues of the liver, heart, and muscle histologically reveals

  • Noticeably enlarged hepatocytes with inclusions that are periodic acid-Schiff (PAS) positive and diastase-resistant traits are typical of the improperly branched glycogen observed in GSD IV. Within the reticuloendothelial system (RES), foamy histiocyte infiltrates with intracytoplasmic deposits have been observed often. Wide fibrous septa and altered hepatic architecture are signs of interstitial fibrosis.

  • Some individuals exhibit fine fibrillary aggregates of electron-dense, the amylopectin-like substance within the cytoplasm of hepatocytes.

• Molecular Genetic Testing - Mutation in the GBE1 gene is assessed by molecular genetic testing.

• Glycogen Branching Enzyme (GBE) - Reduced GBE enzyme activity.

How Is GSD IV Disease Treated?

The treatment for GSD IV differs based on the manifestations.

• Hepatic (Liver) Manifestations - Liver transplantation is the only treatment for people with the progressive hepatic variant of GSD IV who develop liver failure. The prognosis is poor for those with GSD IV who have a liver transplant due to the high risk of morbidity and mortality, which is partially linked to the extrahepatic symptoms of GSD type IV, particularly cardiomyopathy.

• Neurologic Manifestations - Children who exhibit motor developmental delay and have skeletal myopathy or hypotonia should evaluate their development and receive physical treatment as necessary.

• Cardiac Manifestations - A cardiologist should be consulted for patients who have cardiomyopathy. Cardiovascular transplantation may be an option for those with severe cardiomyopathy brought on by glycogenosis. However, before choosing this course of treatment, it is essential to consider any potential risks, such as myopathy, liver failure, and cachexia (wasting syndrome, which causes skeletal muscle and fat loss).

How Can Secondary Complications Be Prevented in GSD IV?

The secondary complications can be prevented.

• Providing adequate dietary intake based on regular assessments and recommendations from a nutritionist with experience managing children with liver disease can prevent nutritional shortages (for example, fat-soluble vitamins).

• It is advised that a coagulation profile be evaluated before surgical procedures and that fresh frozen plasma be administered preoperatively as necessary because bleeding due to coagulopathy (bleeding disorder) can occur, especially with surgical procedures.

Conclusion

At-risk family members can be checked if the GBE1 pathogenic mutations have been found in an affected family member so that those with them can be examined for liver, skeletal muscle, and heart involvement. This will enable early detection and management of disease manifestations.