In Type IV GSD there is not an increased amount of glycogen in the tissues, as in other forms of GSD. Instead, the body produces less-branched, insoluable glycogen in the body's cells, because there is a genetic deficiency of the branching enzyme. As the accumulation of this structurally abnormal glycogen increases, it impairs the function of certain organs and tissues, especially the liver and muscles, and triggers the body’s immune system to attack these tissues. This normally results in severe cirrhosis (scarring) of the liver as well as other organs, such as muscle. GSD IV is estimated to occur in 1 in 600,000 to 800,000 individuals worldwide and accounts for approximately 3 percent of all cases of glycogen storage diseases.
A baby with the typical Type IV GSD appears to be normal at birth. The first indication of a problem is a "failure to thrive". The rate of growth and mental progress of the baby stops at a certain point and does not continue normally. The abdomen expands because the liver and spleen enlarge, there is little weight gain, and muscles develop poor tone. The course of the disease is one of progressive cirrhosis of the liver and the problems associated with this. Death typically occurs by five years of age. The central problem is liver failure. Occasionally, patients with liver problems do not develop cirrhosis and have survived well into adulthood.
Recently, patients with various neuromuscular involvements have been recognized who have been very different from the typical presentation. There are patients whose problems are primarily related to muscle and nervous systems with or without liver problems. Some babies develop severe muscle wasting and poor tone and die of heart failure and breathing difficulty at birth or in early infancy. Patients with muscle and heart problems which developed in late childhood and patients with central and peripheral neuropathy noted in adulthood (adult polyglucosan body disease) have also been noted.
Treatment for Type IV glycogen storage disease has been aimed at the failing liver, which has been symptomatic. For some individuals, maintaining normal blood sugar levels and adequate nutrient intake may improve liver function and muscle strength. Several patients with progressive liver failure have had successful liver transplants; however, after transplant, muscle and heart disease may still be a problem. There is currently no treatment for muscle and nervous system problems.
The branching enzyme is present in cultured amniotic fluid cells, and prenatal diagnosis can, and has been, carried out. The disease is transmitted as an autosomal recessive disorder, each parent being a carrier. Carriers can be detected using white blood cells from a peripheral blood sample, as well as cultured skin fibroblasts.
The gene that encodes the branching enzyme has been isolated and several animal models (mouse and cat) of GSD IV have been developed. Currrent treatment approaches are bing actively tested in animal disease models using gene-based therapy and small molecule drugs. It is hoped that these treatment will soon change the outcome of this disease.