1. Background

• amylo-1,6-glucosidase is an enzyme in the glycogenolytic path-way which helps convert glycogen to lactate by disrupting the 1,6 linkages between glycosyl units ("debrancher enzyme")
• in Forbes Disease:
  • an excess amount of glycogen was first noted in the liver and muscles of affected patients in 1952
  • deficiency of amylo-1,6-glucosidase was first noted in 1956
  • the subclassification of Forbes Disease is confusing due to the identification of several biochemical subtypes based upon tissue variability:
    • liver > muscle (skeletal, cardiac)
    • in most cases the liver is primarily affected but when the disease is generalized, muscle (skeletal and cardiac) are also involved to varying degrees
    • ? infantile vs childhood vs adult forms
    • ? variable genotype mutations -> phenotype variability (tissue mosaicism)

2. Genetic Defect

• genetic defect -> deficiency of amylo-1,6-glucosidase activity -> accumulation of limit dextrin and a decline in glucose-1-phos- phate and, subsequently, lactate production
• there may also be a deficiency of amylo-1,4->1,4-glucantrans-ferase (another "debrancer enzyme")
• two clinical variants:
  Type I - Infantile Form
  Type II - Juvenile Form

1. Muscle Biopsy

• increased glycogen deposits inside the sarcolemmal membrane and between myofibrils

2. Liver Biopsy

• increased glycogen deposits
• fibrous septa but usually no cirrhosis
• paucity of intracellular lipid droplets

1. Type I (Infantile Form)

• manifests in first few months of life
  • hepatomegaly +/- hypoglycemia
  • infantile hypotonia with muscle weakness and poor head control - +/- cardiomegaly
  • failure to thrive

2. Type II (Juvenile Form)

1. Serum

• rarely hypoglycemic, normal lactate, ketones, lipids
• conjugated hyperbilirubinemia
• no acidosis

2. EKG

• can be normal or abnormal

3. Chest X-Ray

• cardiomegaly

4. Ischemic Exercise (Lactate) Test

• results similar to those found in McArdle Disease (i.e., reduced or absent rise in blood lactate)

5. Blood Glucose Test

• if glycogen is given 2hrs after a meal - increase glucose levels
• if glycogen is given after an overnight fast - glucose levels remain flat (distinguishes this GSD from GSD I where the glucose level re-mains flat after both procedures)

6. Diagnosis

• deficiency of amylo-1,6-glucosidase activity on muscle or liver biopsy, cultured skin fibroblasts, or erythrocytes

1. Supportive

• multidisciplinary approach
  • Paediatrics - moniter hepatomegaly and hypotonia, promote ambulation and physiotherapy, ? high-protein diet and raw corn starch
  • Cardiology - moniter cardiomegaly
  • Genetics - genetic counselling, prenatal diagnosis (cultured amniotic fluid cells display a decrease in amylo-1,6-glucosidase activity)

2. Prognosis

• good with benign course especially when the disease is confined to the liver