Genetics of Glycogen-Storage Disease Type IV Clinical Presentation

The classic presentation of glycogen-storage disease type IV (GSD IV) involves development of hepatosplenomegaly and failure to thrive in the first year of life.

Patients with progressive liver cirrhosis and associated portal hypertension may also present with the following:

• Pruritus

• Fatigue

• Anorexia

• Weakness

• Jaundice

• Peripheral edema

• Epistaxis

• Easy bruising and bleeding

Hepatic encephalopathy may cause lethargy, disorientation, or coma. Patients may present with hematemesis due to bleeding esophageal varices.

Patients who are mildly affected with nonprogressive liver disease or early liver cirrhosis may be asymptomatic.

The perinatal form of glycogen-storage disease type IV may include a history of fetal hydrops, cervical cystic hygroma, decreased in utero fetal movements, and severe hypotonia and cardiomyopathy at birth, leading to death in the neonatal period. ^{[1, 2]} Cases of a severe subtype of the perinatal form with fetal akinesia, arthrogryposis, pterygia, and severe skeletal muscle degeneration with onset in the second trimester of pregnancy have been reported. ^[3]

A milder congenital variant is associated with isolated hypotonia and gross motor delay, without hepatic or cardiac involvement.

Patients with muscle involvement may present with muscle weakness, fatigue, and muscle atrophy.

Patients with glycogen-storage disease type IV whose conditions involve associated dilated cardiomyopathy may present with the following:

• Failure to thrive

• Fatigue

• Irritability

• Anorexia and feeding problems

• Diaphoresis

• Dyspnea

• Orthopnea

• Edema

Patients with central and peripheral nerve involvement (eg, adult polyglucosan body disease [APBD]) may present with the following:

• Muscle weakness

• Fatigue

• Gait disturbances (eg, spastic paraplegia)

• Voiding difficulties (eg, neurogenic bladder)

• Peripheral neuropathy

• Mild cognitive impairment and dementia

A physical examination of patients with the classic form of glycogen-storage disease type IV reveals evidence of liver failure and portal hypertension.

Patients with other forms of glycogen-storage disease type IV present with symptoms of affected organ or tissue dysfunction. Affected areas include the heart, peripheral muscle, or CNS and peripheral nervous systems.

Failure to thrive and growth delay may be evident.

Pallor and pale conjunctiva may be noted in patients with anemia.

Jaundice may result from hyperbilirubinemia secondary to decreased hepatic excretory function.

Petechiae and ecchymoses may be observed in patients with thrombocytopenia secondary to splenic sequestration and decreased coagulation factors from hepatic failure.

Peripheral edema may result from decreased hepatic synthesis of albumin or heart failure.

The abdomen may protrude. Hepatomegaly is often present, with increased liver span and a firm, nontender liver edge. In addition, ascites, splenomegaly, and a prominent abdominal venous pattern develop in patients with associated portal hypertension.

Hepatomegaly may be mild or absent in patients with nonprogressive liver disease.

Evidence of early cardiomyopathy includes the following:

• Decreased peripheral perfusion

• Decreased pulse pressure

• Tachycardia

• Hepatomegaly

• Peripheral edema

• Systolic murmur due to valvular incompetence

• Gallop rhythm

• Abnormal lung auscultatory findings

• Costal and subcostal retractions

• Increased jugular venous pressure

• Periorbital edema in infants

Patients with glycogen-storage disease type IV that involves the muscles may have muscle atrophy, weakness, and decreased strength.

Patients with the severe perinatal form of glycogen-storage disease type IV often exhibit severe muscle involvement, including biventricular cardiac dysfunction and facial weakness. ^[4]

Patients with peripheral nerve involvement typically present with neurogenic bladder, spastic paraplegia, or axonal neuropathy. ^[5] They may exhibit decreased or absent deep tendon reflexes and a peripheral neuropathy with sensory loss, primarily in the lower extremities. At times, the disorder may mimic signs of amyotrophic lateral sclerosis.

Patients with CNS involvement and leukoencephalopathy may exhibit mild cognitive impairment or dementia.

An affected fetus or stillborn baby may exhibit arthrogryposis and fetal hydrops.

Examination of an affected neonate may reveal severe hypotonia; shallow respirations; muscle atrophy; and signs of heart failure such as tachypnea, poor peripheral perfusion, low blood pressure, and periorbital edema.

All forms of glycogen-storage disease type IV result from defects in the gene that encodes for the glycogen-branching enzyme (GBE1) located on chromosome band 3p12. The function of this enzyme is to increase the number of branch points during glycogen synthesis. The branched nature of the glycogen molecule is important for its compact nature and solubility within the cell. The absence of this branching activity results in abnormal glycogen with long, unbranched outer chains that resemble amylopectin, which is a glucose polymer that is a major storage polysaccharide in legumes. ^{[6, 7]}

Deficient branching enzyme activity and mutations in the gene that encodes for the glycogen-branching enzyme may be generalized or isolated to a specific cell line or tissue.

Specific mutations have been identified in patients with classic, perinatal, and nonprogressive hepatic forms of glycogen-storage disease type IV. Further studies to determine genotype-phenotype correlations are in progress.

A homozygous GBE1 mutation (Tyr329Ser) is the most common finding in Ashkenazi Jewish patients.