Glycogen Storage Diseases Types I-VII Clinical Presentation

Updated: Dec 01, 2022
  • Author: Catherine Anastasopoulou, MD, PhD, FACE; Chief Editor: George T Griffing, MD  more...
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GSD type I

The earliest signs of disease may develop shortly after birth and are usually symptoms of hypoglycemia. Patient's may present with irritability, pallor, cyanosis, hypotonia, tremors, loss of consciousness, apnea and seizures. The median age of symptom presentation is usually four to six months. 

Some children have diarrhea due to pseudocolitis.

GSD type II

Symptoms of the infantile form usually begin in infants at the end of the second month of life, with profound hypotonia and heart failure. Muscle weakness progresses rather rapidly, manifesting as respiratory and feeding difficulties.  An early onset “nonclassic” phenotype has also been described in these cases, hypotonia without cardiomyopathy develops during the first and second year of life.

In the juvenile form, the initial clinical symptoms appear in persons aged 1-15 years. Retarded motor development, hypotonia, and muscle weakness due to slowly progressive skeletal muscle disease characterize the juvenile form. Intellectual development is normal. Atony of the anal sphincter and enlargement of the urinary bladder can be found in only a minority of children.

The adult form develops in persons aged 10-30 years and, less commonly, later. Its course progresses slowly. Dyspnea due to the involvement of respiratory muscles and difficulties in climbing up the stairs caused by proximal myopathy are the leading clinical manifestations. In one third of patients, the initial symptoms are somnolence, morning headaches, orthopnea, and exertional dyspnea. Weakness of the respiratory muscles, particularly the diaphragm, causes these symptoms. [38]

GSD type III

The first manifestations of the disease usually appear in infants one year of age, although in milder variants, the onset may be delayed into childhood. The symptoms are much less severe than in GSD type 1, and only about half of the patients present with severe hypoglycemia. Hepatomegaly is the most common presenting symptom on routine examination which then prompts further investigation. Other signs such as growth retardation, hyperlipidemia and fasting ketotic hypoglycemia can also be seen. [7, 18]

Liver disease is less common in adolescents and adults. In childhood, weakness and muscle fatigue secondary to skeletal myopathy is less prominently seen. This is in contrast to adulthood where muscle weakness is more commonly seen because of progression of muscle damage and disease . Cardiovascular abnormalities can further dominate the clinical presentation of the disease depending on severity of cardiac involvement. Patients with GSD IIIa may present with hypertrophic cardiomyopathy in which the disease course can range from asymptomatic to severe. [6]

GSD type IV

Children affected with GSD type IV are born without signs of the disease, although some of them may have a dysmorphic face. However, in the weeks after birth, failure to thrive, hypotonia, and atrophy of the muscles are noted. (see physical)

GSD type V

The classic form appears in persons aged 10-20 years, most in first decade of life. Degree of exercise intolerance varies per individual. Symptoms are usually exacerbated with sustained aerobic or isometric exercise. [20]  Patients commonly report fatigue during physical exertion, muscle cramps, and later, muscle weakness and burgundy red–colored urine. Patients with GSD type V may also present with the "second wind phenomenon" in which patients have quick relief of muscular fatigue with rest and are then able to resume physical activity without significant symptoms. [20]

GSD type VI

Symptoms, if present, are minimal. Often, patients seek help for retarded growth and prominent hepatomegaly. Hypoglycemia ranges from mild to severe, with ketotic hypoglycemia after fasting. Hypoglycemia can present during pregnancy. 

GSD type VII

Similar to that of GSD type V, intolerance of physical activity, muscle cramps, and burgundy red–colored urine occur during a rhabdomyolysis episode. [22]   

Attacks of rhabdomyolysis may be associated with nausea and vomiting, and more often than not, a meal rich in carbohydrates is consumed beforehand.


Physical Examination

GSD type I

A leading sign of GSD type I is enlargement of the liver and kidneys. Enlargement of the abdomen due to hepatomegaly can be the first sign noted by the patient's mother. During the first weeks of life, the liver is normal size.It enlarges gradually thereafter, and in some patients, it even reaches the symphysis.  

Because of fat deposition in the cheeks, patient's characteristically resemble a doll's face. See the image below. 

An infant with glycogen storage disease type Ia. N An infant with glycogen storage disease type Ia. Note the typical facial aspect resembling a doll's face.

Mental development proceeds normally.

Growth failures, as described as short stature and thin legs, are commonly seen in children affected by GSD type 1. Affected children never gain the height otherwise expected from the genetically determined potential of their families. The patient's height is usually below the third percentile for their age. The onset of puberty is delayed. See the image below.

A child with glycogen storage disease type Ia. A child with glycogen storage disease type Ia.

Skin and mucous membrane changes include the following:

  • Eruptive xanthomas develop on the extensor surfaces of the extremities.

  • Tophi or gouty arthritis may occur. Uric tophi often have the same distribution as xanthomas.

  • Spider angiomas may be present.

  • Perianal and gingival abscesses of the oral mucosa and gums may be observed. Aphthous ulcers are often present in patients with GSD type Ib.

  • Perianal erythema and erosions may occur in patients with prolonged diarrhea due to pseudocolitis.

  • In a 2002 report, Visser et al [39]  presumed that the main cause of disturbed intestinal function is loss of the integrity of the mucosal barrier, which occurs as a result of inflammation, and loss of neutrophil function, which often occurs in patients with GSD lb.

Risk factors and adverse events are as follows:

  • Foods rich in fructose, galactose, and triglycerides adversely affect the long-term complications caused by lactic acidosis, hyperuricemia, and hyperlipidemia.

  • Hypoglycemia and infections are frequent.

GSD type II

Heavy deposits of glycogen in the heart, liver, and tongue characterize the infantile form; as a result of the deposits, these tissues enlarge.

Conspicuous cardiomegaly with cardiomyopathy and heart failure may be present. Macroglossia, tongue fasciculation and moderate hepatomegaly may be noted.

Generalized severe hypotonia and muscle weakness that involves skeletal and respiratory muscles, as well as. delayed motor milestones, feeding and swallowing difficulties are characteristics.  The affected skeletal muscles are firm on palpation and, occasionally, hypertrophic. In some patients. Signs of respiratory insufficiency are due to the involvement of respiratory musculature. Spontaneous movements are scarce, and painful stimuli cause weak motor reactions. Tendon reflexes are diminished or absent. Mental functions are retained.

In the CNS, the disease primarily affects the nuclei of the brainstem and the cells of the ventral horn of the spinal cord. Mental functions are preserved.

Juvenile form

Respiratory insufficiency and hypotonia largely of the proximal musculature are present. Macroglossia, cardiomegaly, cardiomyopathy, and hepatomegaly usually are absent.

Adult form

Proximal muscle weakness (difficulty rising from a chair or climbing stairs). Muscle volume is decreased, and tendon reflexes are diminished.  Waddling gait, Gower sign, Trendelenburg sign are seen, the visceral organs are not affected; however, intracranial aneurysms are possible because of glycogen deposits in the smooth muscle cells of the cerebral arteries. Cardiomyopathy is not a feature of the adult form. 

GSD type III

GSD type III is a heterogeneous disease. Two subtypes exist: GSD type IIIa and GSD type IIIb. In most patients, the liver is enlarged. In some children, growth retardation, renal tubular dysfunction, liver adenomas, liver cirrhosis can be observed.

GSD type IIIa is more common (approximately 85%) and prognostically more unfavorable than other forms. Hepatomegaly and/or splenomegaly are present with elevated liver transaminases. Muscular weakness and atrophy, particularly of the girdle and limb musculature, may be observed. Cardiomegaly and cardiomyopathy may occur which can lead to heart failure and possibly sudden death.Cardiac and skeletal muscle abnormalities taking on a progressive course and possibly appearing at different ages (from early childhood to late adulthood) may be noted.

GSD type IIIb is less common (approximately 15%) although prognostically more favorable than other forms. The liver is the only organ involved. Hepatosplenomegaly is moderate. Mild fibrosis and micronodular cirrhosis of the liver are rare and often clinically silent. Hepatomegaly is pronounced during childhood but usually normalizes at puberty. Growth is accelerated at puberty; therefore, most patients reach their expected height.

GSD type IV

Presentation varies depending on the mutation, however, 5 frequent subtypes have been identified: [19]

Hepatic predominant forms:

  • Classic (progressive) hepatic subtype. Failure to thrive, hepatomegaly, liver dysfunction, progressive liver scarring with portal hypertension, ascites, and esophageal varices, jaundice, hypotonia, and cardiomyopathy. Hypoglycemia may develop later in the course of the disease. Disease is evident during the first 18 months of life. Death typically by age five years from liver failure
  • Non-progressive hepatic subtype. Liver dysfunction, myopathy, and hypotonia in childhood.

Neuromuscular predominant forms:

  • Fatal perinatal neuromuscular subtype. Presents in utero with fetal akinesia deformation sequence (FADS):  Decreased fetal movements, multiple contractures, polyhydramnios, hydrops fetalis, hypotonia, cardiac dysfunction and perinatal death. 
  • Congenital neuromuscular subtype. Presents with severe hypotonia at birth, respiratory distress, dilated cardiomyopathy, weakness, muscle atrophy and early infantile death. 
  • Childhood neuromuscular subtype. Presents with skeletal myopathy (weakness, fatigue, exercise intolerance, atrophy), and occasionally with dilated cardiomyopathy, arrhythmias and heart failure.
  • Adult Polyglucosan body disease. Rare variant, presents with upper and lower motor neuron symptoms, urinary incontinence, sensory deficits, gait disturbances, autonomic dysfunction and cognitive impairment.

GSD type V

In a milder variety, the first symptoms and signs may appear late, even in elderly patients. 

Forms clinically expressed in the first years of life occur with muscle hypotonia and generalized muscle weakness and occasionally lead to respiratory insufficiency.

Myoglobinuria from repeated strenuous exercise can be a cause of renal failure.

GSD type VI

GSD type VI is a benign disease.

At times, hepatomegaly is incidentally noted during an investigation of the child's slow growth.

Skeletal and cardiac muscles are unaffected.

With age, the size of the liver decreases and normalizes at or around puberty.

No intellectual abnormalities.

GSD type VII

GSD type VII is more severe than GSD type V.

Rhabdomyolysis with renal failure is common.

In some patients, erythrocyte hemolysis occurs.

Jaundice is apparent in severe hemolysis.

Two rare varieties of GSD type VII exist. One form occurs in infants with hypotonia and weakness of the extremity muscles; this form progresses in severity, with a lethal outcome in early childhood. The other form occurs in young adults or older persons; this form progresses slowly, and its clinical presentation is dominated by the weakness of the different muscle groups rather than the muscle cramps and myoglobinuria.