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)

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 as below:

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.
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 Adult Polyglucosan Body Disease (APBD)

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 pathologic 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.OMIM
• The disease often leads to premature death.

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 intracytoplasmic 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.

Genetics

• 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).

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. 

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 frequency of all glycogen storage diseases is estimated to be 1 in 20,000 to 25,000 live births, while GSD IV is estimated to occur in 1 in 600,000 to 800,000 individuals worldwide.  NORD GHR https://ghr.nlm.nih.gov/condition/glycogen-storage-disease-type-iv#statistics

Gender

• Males and females appear to be affected in relatively equal numbers because the deficiency of glycogen-branching enzyme activity is inherited as an autosomal-recessive trait.

Race

• Familial aggregation is observed in about 30% of adult polyglucosan body disease cases, especially among Ashkenazi Jewish populations.

Risk Factors

• As GSD type IV is an inherited disease with autosomal recessive pattern, a positive family history is a potent risk factor.

• Each sibling of a diseased individual has a 25% probability of being affected, a 50% probability of being a carrier, and a 25% probability of being unaffected and not a carrier.

Screening

• Currently, there is no screening guideline recommendation.
• 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 IV is a very rare disorder.

• Liver transplantation has been found to prevent progression of the disease.
• 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 is confirmed by demonstration of glycogen branching enzyme (GBE) deficiency in liver, muscle, or skin fibroblasts, and/or

•  Molecular genetic testing of GBE1 gene for mutations https://www.ncbi.nlm.nih.gov/books/NBK115333/

History and Symptoms

·      Classically, the patient presents in their first year of life with complaints of failure to thrive and hepatosplenomegaly.[17]

·       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. PubMed: 8830177 [PubMed: 3162725]

·      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. PMID 15669676

·      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.[20] [21]

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 protuberance

·       Hepatosplenomegaly [17]

·       Signs and symptoms of portal hypertension [17]

Newborns with perinatal form of disease may show:

·       Poor respiratory effort at birth [7]

·       Hyporeflexia [PubMed: 15452297]

·       Severely decreased muscle tone [PubMed: 4502299] [PubMed: 8059607]

Patients with ‘late childhood form’ of disease may have:

·      dysmorphic features [PubMed: 7683169]

·      myopathic faces, hypotonia, and waddling gait with hyperlordosis [PubMed: 15452297]

Laboratory Findings

• Liver functions tests:
  • ALT and AST are typically elevated in the hepatic subtype of disease.https://www.ncbi.nlm.nih.gov/books/NBK115333/#gsd4.Diagnosis
  • Decreased albumin levels, prolonged partial thromboplastin time (PTT) and prothrombin time (PT) point to progressive liver dysfunction. https://www.ncbi.nlm.nih.gov/books/NBK115333/#gsd4.Diagnosis

• GBE activity
  • Decreased activity of glycogen branching enzyme is found in the liver, leukocytes, erythrocytes and fibroblasts [PMID:11949934] PMID:2972882 

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

• 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. PMID:1067751 
  • The deposits appear precipitated and are centrally placed in the hepatocytes, while nuclei are eccentric in position. PMID:1067751 
  • . PMID:1067751 

• Chitotriosidase levels:
  • Plasma chitotriosidase levels are noted to be elevated in GSD Type IV. PMID: 15669690

X-ray

• Chest radiography is usually not vital in establishing diagnosis.
• In patients with heart involvement, pleural effusions and cardiomegaly may be observed. PMID:3474393

Electrocardiogram

• Although there are no specific EKG findings associated with the disease, after the initial diagnosis, a baseline electrocardiogram is suggested to access for cardiomyopathy. GeneReview

Echocardiography

• In patients with symptoms of heart failure, echocardiography may show evidence of cardiomyopathy. PMID:20833045

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 required.
• If done to investigate complications of the disease, cirrhotic changes in liver parenchyma may be observed.

MRI

• Magnetic resonance imaging is routinely not required for the diagnostic purposes.
• When done in patients with 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. (ISSN: 1531-8249)MedSke

Treatment

Medical Therapy

• There is no specific treatment available for the disease.
• The mainstay 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. PMID :10603098

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 multisystem 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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