Glycogen storage disease type IV

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vellayat Ali M.B.B.S[2]

Synonyms and keywords: Andersen Disease; Brancher deficiency; Amylopectinosis; Glycogen branching enzyme deficiency; Glycogenosis IV; Adult polyglucosan body disease (APBD); Glycogen storage disease type 4; GSD type IV; GSD IV; GSD type 4; GSD 4.

Overview

Glycogen storage disease type IV (GSD IV) is a rare inherited disorder affecting the glycogen metabolism. In 1956, DH Andersen, an American pathologist and pediatrician reported the first clinical case of the disease. It is caused by mutations in the GBE1 gene, which then results in variable deficiency of glycogen branching enzyme (GBE), an enzyme responsible for the branched structure of glycogen molecules. Due to decreased activity of GBE, abnormal glycogen molecules with less branches is synthesized which then precipitates in various body tissue, especially the liver, muscle, and heart. Clinically, GSD IV manifests as different types; the classic hepatic subtype, and the neuromuscular subtype. Based on clinical features and age of onset, the neuromuscular type can be further divided into four forms including perinatal form, congenital form, late childhood form, and the adult form. The classic hepatic subtype presents with failure to thrive during first few months after birth, and then, progresses to liver dysfunction. Unless a liver transplant is performed, death due to liver cirrhosis occurs by the age of 5 years. The perinatal neuromuscular subtype presents in utero with polyhydramnios, hydrops fetalis, and decreased fetal movement. The congenital neuromuscular subtype presents in the newborn period with severe hypotonia, decreased reflexes, and dilated cardiomyopathy. The childhood neuromuscular subtype may present at any age during childhood with myopathy and cardiomyopathy which progresses to congestive heart failure. The adult neuromuscular form may present as isolated myopathy or adult polyglucosan body disease (APBD). The diagnosis requires demonstration of GBE deficiency in liver, muscle, or skin fibroblasts, and/or gene testing for mutations in GBE1. The management is multidisciplinary, and should be provided by a team comprising of a pediatrician, a cardiologist, a neurologist, a nutritionist, and a geneticist.

Historical Perspective

• In 1952, B Illingworth and GT Cori observed accumulation of an abnormal glycogen (resembling amylopectin) in the liver of a patient with von Gierke's disease. They postulated this finding to a different type of enzymatic deficiency, and thus to a different type of glycogen storage disease.

• In 1956, DH Andersen, an American pathologist and pediatrician, reported the first clinical case of the disease as "familial cirrhosis of the liver with storage of abnormal glycogen".
• In 1966, BI Brown and DH Brown clearly demonstrated the deficiency of glycogen branching enzyme (alpha-1,4-glucan: alpha-1,4-glucan 6-glycosyl transferase) in a case of Type IV glycogenosis.

Classification

There is no established system for the classification of GSD Type IV. The deficiency of GBE affecting liver, brain, heart, and skeletal muscles leads to variable clinical presentations. Based on organ/tissue involvement, age of onset and clinical features, Andersen disease can be segregated into various forms :

Form of Presentation		Age of Onset	Clinical Features
Classic Hepatic Form		0-18 mo	Infants with classic hepatic form present with failure to thrive, hypotonia and hepatosplenomegaly. The disease progresses to portal hypertension, ascites, and liver failure, leading to death by 5 years of age. A non-progressive form is also known, patients survive without progressive liver disease.
Neuro- Muscular Form	Perinatal	In utero	Prenatal symptoms include, polyhydramnios, hydrops fetalis, and decreased fetal movement; at birth severe hypotonia is observed requiring mechanical ventilation for respiratory support. Cardiac findings like progressive cardiomyopathy may also be present.
	Congenital	At birth	Newborns may present with severe hypotonia, hyporeflexia, cardiomyopathy, depressed respiration and neuronal involvement, leading to death in early infancy.
	Late childhood	0-18 yrs	Presents in childhood at any age with myopathy as exercise intolerance, and cardiopathy as exertional dyspnea; and congestive heart failure in progressed cases.
	Adult	>18-21 yrs (any age in adulthood)	May present as isolated myopathy or as adupolyglucosansan body disease (APBD)

Pathophysiology

Pathogenesis

• Glycogen storage disease type IV is an autosomal recessive genetic disorder which results due to deficiency of glycogen branching enzyme (GBE).
• During glycogenesis, the branching enzyme introduces branches to growing glycogen chains by transferring α-1,4-linked glucose monomers from the outer end of a chain into an α-1,6 position of the same or neighboring glycogen chain.
• Deficiency of GBE affects the branching process, yielding a polysaccharide which has fewer branching points and longer outer chains, thus resembling amylopectin. This new amylopectin-like structure is also known as polyglucosan.
• The enzyme deficiency affects all the bodily tissues; but liver, heart, skeletal muscles, and the nervous system are mostly affected.
• The abnormally branched glycogen accumulates as intra-cytoplasmic non membrane-bound inclusions in hepatocytes, myocytes, and neuromuscular system; where it increases osmotic pressure within cells, causing cellular swelling and death.
• The altered structure also renders glycogen to become less soluble, and this is thought to lead into a foreign body reaction causing fibrosis, and finally culminating in liver failure.
• In skeletal muscle, accumulation leads to muscle weakness, fatigue, exercise intolerance, and muscular atrophy.
• The heart may be affected with a wide spectrum of cardiomyopathy; from dilated to hypertrophic and from asymptomatic to decompensated heart failure may occur.
• Although exact mechanism for this pathology is not known, glycogen deposition in the myocardium is thought to initiate signaling pathways which cause sarcomeric hypertrophy, resulting in hypertrophic cardiomyopathy.

Adult Polyglucosan Body Disease (APBD)

• Adult polyglucosan body disease is one of the neuromuscular variant of GSD Type IV.
• It is a late-onset, slowly progressive disorder of the nervous system GBE deficiency in a subgroup of patients of Ashkenazi Jewish origin.
• Typically, the first clinical manifestation is of urinary incontinence secondary to neurogenic bladder.
• This is followed by gait disturbance (due to spastic paraplegia) and lower limb paresthesias.
• Patients deteriorate slowly over years and lose ability to ambulate independently, and develop paralysis of the upper limbs as well.
• Progressive dementia is also seen in these patients.
• The pathological hallmark of the disorder is the widespread accumulation of round, intracellular polyglucosan bodies throughout the nervous system, which are confined to neuronal and astrocytic processes.
• The disease often leads to premature death.

Causes

• The cause of GSD type IV is variable deficiency of glycogen branching enzyme (GBE).

• The deficiency is due to various mutations of GBE1 gene encoding the single polypeptide protein.
• Glycogen branching enzyme is a 702 amino acid protein encoded by GBE1 gene mapped to chromosome 3p12.2.
• Mutations in the GBE1 are responsible for enzymatic deficiency, and so far 40 pathogenic variants have been identified in individuals with GSD IV or adult-onset polyglucosan body disease (APBD).

Differentiating from Other Diseases

• Comparisons may be useful for a differential diagnosis as a number of other disease conditions with clinical features may present similar to those associated with GSD Type IV.
• Presenting as hepatomegaly in infancy, the following glycogen metabolism disorders should be differentiated from GSD Type IV; 
  • GSD Type I
  • GSD Type III
  • GSD Type VI
  • Hepatic phosphorylase b kinase deficiency

• Metabolic disorders presenting with muscle weakness/myopathy during infancy should also be considered;
  • Muscle glycogen synthase deficiency (GSD0b)
  • Lysosomal acid maltase deficiency (GSD II)
  • Glycogen debrancher deficiency (GSD III)
  • Muscle phosphorylase deficiency (GSD V)
  • Aldolase A deficiency (GSD XII)
  • Glycogenin-1 deficiency (GSD XV)

Epidemiology and Demographics

Frequency

• The incidence of GSD type IV is approximately 0.13 to 0.17 per 100,000 individuals worldwide.

Gender

• GSD type IV affects men and women equally.

Race

• Adult polyglucosan body disease usually affects individuals of the Ashkenazi Jewish population. Familial aggregation is observed in about 30% of cases.

Risk Factors

• The most potent risk factor in the development of glycogen storage disease type IV is a sibling with glycogen storage disease type IV.

Screening

• Currently, there is no screening guideline recommended.
• In some cases, the disease may be diagnosed prenatally via chorionic villus sampling (CVS) and amniocentesis.

Prenatal Diagnosis

• After genetic confirmation of the affected cases, future pregnancies can be monitored by determining branching enzyme activity and DNA analysis of chorionic villi or cultured amniocytes.

• Histological analysis of placental tissue may also be used in prenatal diagnosis of the disease.

Natural History, Complications, and Prognosis

• GSD type IV is a very rare disorder.

• Liver transplantation has been found to prevent progression of the disease.
• Common complication of GSD type IV include liver failure which presents as ascities, portal hypertension, and coagulopathy.
• Classic hepatic form begins in first year of life, progresses to hepatic failure, and death occurs by 5 years of age.

• Most children with this condition die before two years of age, in rare cases progression to liver dysfunction does not occur.

Diagnosis

• Glycogen storage disease type IV should be suspected in a patient based on clinical features and finding abnormally branched glycogen accumulation in muscle or liver tissue.

Diagnostic Study of Choice

The diagnosis of GSD type IV is confirmed by using either or both of the following:

• Demonstration of glycogen branching enzyme (GBE) deficiency in liver, muscle, or skin fibroblasts.

•  Molecular genetic testing of GBE1 gene for mutations.

Liver biopsy

• Liver biopsy shows accumulation of abnormal glycogen in hepatocytes. The deposits stain strongly positive with periodic acid-Schiff (PAS), appear brown with iodine, and are only partially digested by diastase.
• The deposits appear precipitated and are centrally placed in the hepatocytes, while nuclei are eccentric in position.

History and Symptoms

• Classically, the patients present in their first year of life with history of failure to thrive and hepatosplenomegaly.
• As the disease progress towards cirrhosis, features of hepatic failure become evident.
• Rarely in some children, hepatomegaly is the only presentation and disease does not progress to liver failure.
• In perinatal variant, affected newborns may have a prenatal history of polyhydramnios, reduced utero fetal movements, and fetal hydrops. At birth, lack of active movements, sucking, and swallowing is noted.
• Individuals with late childhood form usually present in the second decade of life with complaints of exercise intolerance and exertional dyspnea secondary to muscle involvement and cardiomyopathy respectively.

Physical Examination

Findings on physical examination of patients with glycogen storage disease type IV vary with respect to the disease variant and organ system involved.

• In infants with the classic (hepatic) form of GSD type IV, findings depicting liver involvement predominate:
  • Abdominal distension
  • Hepatosplenomegaly
  • Signs and symptoms of portal hypertension

• Newborns with perinatal form of disease may show:
  • Poor respiratory effort at birth
  • Hyporeflexia
  • Severely decreased muscle tone

• Patients with late childhood form of disease may have:
  • Dysmorphic features
  • Myopathic faces, hypotonia, and waddling gait with hyperlordosis

Laboratory Findings

• Liver functions tests:
  • ALT and AST are typically elevated in the hepatic subtype of disease.
  • Progression towards liver dysfunction is suspected if:
    • Decreased albumin levels
    • Prolonged partial thromboplastin time (PTT) and prothrombin time (PT)

• GBE activity
  • Decreased activity of glycogen branching enzyme is found in the liver, leukocytes, erythrocytes and fibroblasts.

• Creatinine kinase (CK) levels:
  • CK levels are usually elevated, demonstrating muscle pathology, in the neuromuscular forms of the disease.

• Chitotriosidase levels:
  • Plasma chitotriosidase levels are elevated in GSD type IV.

X-ray

• There are no X-ray findings associated with GSD type IV. However, chest x-ray may be helpful in diagnosing complication of GSD type IV due to cardic involvement.
• Chest x-ray findings due to cardiac involvement in GSD type IV include:
  • Pleural effusions
  • Cardiomegaly

Electrocardiogram

• There are no electrocardiogram finding associated with GSD type IV. However, after the initial diagnosis, a baseline electrocardiogram is suggested to monitor for cardiomyopathy.

Echocardiography

• There are no echocardiography finding associated with GSD type IV. However, echocardiography may be helpful in diagnosing complication of GSD type IV due to heart failure.
• Echocardiography findings due to heart failure in GSD type IV include:
  • Cardiomyopathy

Ultrasonography

• Abdominal ultrasound examination is done in the initial workup of the disease.
• It may show hepatosplenomegaly and coarse echo pattern of the liver.

CT scan

• CT scan is usually not indicated in GSD type IV.
• However, CT scan may be helpful in diagnosis of complications of the GSD type IV. Cirrhotic changes in liver parenchyma may be observed in CT scan.

MRI

• Magnetic resonance imaging is routinely not indicated for the diagnostic purposes.
• However, MRI may be helpful in diagnosis of CNS involvement and adult polyglucosan body disease (APBD).
• MRI of the head may reveal leukoencephalopathy and cortical atrophy. MRI typically demonstrates:
  • Medullary and spinal atrophy
  • Mild thinning of corpus callosum
  • Symmetric periventricular white matter changes with occipital predominance

Treatment

Medical Therapy

• There is no specific treatment available for the disease.
• The mainstay of therapy is to provide symptomatic and supportive care through coordinated efforts of a multidisciplinary team consisting of healthcare professionals.
• Symptomatic care involves treating manifestations of hepatic dysfunction i.e. ascites, portal hypertension, variceal bleeds, and coagulopathy.
• Once hepatic failure sets in, liver transplantation is the only treatment option available.

Liver transplant surgery

• Liver transplantation is the most effective treatment for patients with classic GSD type IV.
• Like other transplant surgeries, risks include immediate postoperative complications and organ rejection.
• Living donor liver transplant is also a viable option. Long-term follow-up after LT for GSD shows excellent graft and patient survival.
• As GSD type IV is a multi-system disorder, the long-term success of liver transplantation and its effect on the disease progression in other organs is unclear.
• Several patients have reportedly experienced decreased progression after transplant surgery, while few patients developed accumulation of abnormal glycogen in other organs e.g. heart.

References

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