Chapter 71

## Abstract

Abstract

1. Glycogen storage diseases are inherited disorders that affect glycogen metabolism. Virtually all proteins involved in the synthesis or degradation of glycogen and its regulation have been discovered to cause some type of glycogen storage disease. The glycogen found in these disorders is abnormal in quantity, quality, or both. The different forms of glycogen storage disease have been categorized by number in accordance with the chronological order in which these enzymatic defects were identified.

Liver and muscle have abundant quantities of glycogen and are the most commonly and seriously affected tissues. Because carbohydrate metabolism in the liver is responsible for plasma glucose homeostasis, glycogen storage diseases that mainly affect the liver usually have hepatomegaly and hypoglycemia as the presenting features.

In contrast, the role of glycogen in muscle is to provide substrates for the generation of ATP for muscle contraction. The predominant clinical features of glycogen storage diseases that mainly affect the muscle are muscle cramps, exercise intolerance, susceptibility to fatigue, and progressive weakness.

2. Type Ia glycogen storage disease, or von Gierke Disease (MIM 232200), is caused by a deficiency of glucose 6-phosphatase activity in the liver, kidney, and intestinal mucosa, with excessive accumulation of glycogen in these organs. The stored materials in the liver include both glycogen and fat. The clinical manifestations are growth retardation, hepatomegaly, hypoglycemia, lactic acidemia, hyperuricemia, and hyperlipidemia. A variant caused by a defect in the transport of glucose 6-phosphate (type Ib) (MIM 232200) has the additional findings of neutropenia and impaired neutrophil function, resulting in recurrent bacterial infections and oral and intestinal mucosa ulceration. Both type Ia and Ib genes have been cloned and mutations responsible for the diseases identified.

In the past, many patients with type I glycogen storage disease died, and the prognosis was guarded in those who survived. Long-term complications include gout, hepatic adenomas, osteoporosis, renal disease, and short stature. Major progress has been made in managing this disorder. The current treatment of type I glycogen storage disease is nocturnal nasogastric infusion of glucose or orally administered uncooked cornstarch. Both methods are effectively improving growth, reducing hepatomegaly and sustaining the commonly measured metabolic indexes of adequate therapy in patients with type I glycogen storage disease.

Early diagnosis and early initiation of an effective treatment have improved the outcome of the disease, but it is not known if all long-term complications can be avoided by good metabolic control. Some early treated patients who are now adults still develop hepatic adenomas and proteinuria.

3. Type II glycogen storage disease, also known as Pompe Disease (MIM 232300), is caused by a deficiency of lysosomal acid α-glucosidase and is the prototype of an inborn lysosomal storage disease. This disease is described in Chap. 135.

4. Type III glycogen storage disease (MIM 232400) is caused by a deficiency of glycogen debranching enzyme activity. A deficiency of debranching enzyme impairs the release of glucose from glycogen but does not affect glucose released from gluconeogenesis. The glycogen accumulated has a structure that resembles limit dextrin (glycogen with short outer chains).

Most patients with type III glycogen storage disease have both liver and muscle involvement (type IIIa). However, some patients (∼15 percent of all type III cases) have only liver involvement, without apparent muscle disease (type IIIb). During infancy and childhood, both type IIIa and IIIb diseases may be almost indistinguishable from type I disease, as hepatomegaly, hypoglycemia, hyperlipidemia, and growth retardation are similar predominant features. In type III, however, blood lactate and uric acid levels are usually normal, and elevations of liver transaminases are prominent. The liver symptoms in general improve with age and disappear after puberty. Progressive liver cirrhosis and failure however may occur in adulthood. In patients with disease also involving muscle (type IIIa), muscle weakness, though minimal during childhood, can become predominant in adults; these patients show signs of neuromuscular involvement, with slowly progressive weakness and distal muscle wasting. Cardiac muscle is also involved with ventricular hypertrophy a frequent EKG finding.

Treatment of type III disease is symptomatic; if hypoglycemia is present, frequent meals high in carbohydrates, with cornstarch supplements or nocturnal gastric drip feeding, constitute effective therapy. A high-protein diet may also be effective in preventing hypoglycemia as gluconeogenesis is intact in these patients. Currently, there is no effective treatment for the progressive myopathy or cardiomyopathy.

5. Type IV glycogen storage disease (MIM 232500) is caused by a deficiency of branching enzyme activity, which results in the accumulation of glycogen with unbranched, long, outer chains in the tissues. This form of glycogen storage disease typically presents in the first year of life, with hepatosplenomegaly and failure to thrive. Hypoglycemia is rarely seen. Progressive liver cirrhosis with portal hypertension, ascites, esophageal varices, and death, usually occur before the age of 5 years. Liver transplantation has been performed and may be an effective treatment. However, caution should be taken in selecting patients for liver transplantation as a nonpogressive hepatic form of the disease exists and extrahepatic manifestations of the disease may occur after transplantation. In addition to the hepatic form, there are variant forms with neuromuscular presentation.

6. Type V glycogen storage disease, also known as McArdle Disease (MIM 232600), is caused by a deficiency of muscle phosphorylase activity. Symptoms usually appear in adulthood and are characterized by exercise intolerance with muscle cramps that can be accompanied by attacks of myoglobinuria.

Exercise tolerance can be augmented by aerobic training or by oral administration of glucose or fructose. Avoidance of strenuous exercise prevents the symptoms.

7. Type VI (MIM 232700) and type IX (MIM 306000) glycogen storage diseases represent a heterogeneous group of diseases caused by a deficiency of the liver phosphorylase system. In this chapter, we refer to type VI as a defect in liver phosphorylase itself, and type IX as a defect in one of the four subunits of phosphorylase kinase. It should be noted that the latter enzyme deficiency has also been classified as VIa or VIII in the past. Patients with either phosphorylase or phosphorylase kinase deficiencies present in early childhood with hepatomegaly and growth retardation. Hypoglycemia and hyperlipidemia are variable and, if present, usually mild. There is no hyperlactic acidemia or hyperuricemia. Treatment is based on the symptoms with a high-carbohydrate diet and frequent feedings to alleviate hypoglycemia. Most patients require no specific treatment. These are, in general, benign forms of glycogen storage disease. Prognosis is good; adult patients have normal stature and minimal hepatomegaly. In contrast to the other types of glycogen storage disease, which are inherited in an autosomal recessive manner, family studies indicate an X-linked inheritance in most patients with liver phosphorylase kinase deficiency.

Other phosphorylase kinase deficiency variants include an autosomal recessive type that affects both liver and muscle (MIM 261750) or liver only, a myopathic form that resembles type V glycogen storage disease, and an isolated myocardial phosphorylase kinase deficiency (MIM 261740). The clinical heterogeneity can be explained by the presence of four subunits of phosphorylase kinase variably expressed in tissue-specific manners.

8. Type VII glycogen storage disease (MIM 232800) is caused by a deficiency of muscle phosphofructokinase activity. The clinical features are very similar to those in type V glycogen storage disease with the notable exceptions of a compensated hemolytic anemia and early onset myogenic hyperuricemia. In addition to the accumulation of normal glycogen in muscle, an abnormal glycogen, resembling amylopectin, can be found in some muscle fibers.

9. Other glycogenoses discussed in this chapter are glycogen synthase deficiency (MIM 240600), hepatic glycogenosis with renal Fanconi Syndrome (MIM 227810), phosphoglucoisomerase deficiency, muscle phosphoglycerate kinase deficiency (MIM 311800), phosphoglycerate mutase deficiency (MIM 261670), lactate dehydrogenase deficiency (MIM 50000), fructose 1,6-bisphosphate aldolase A deficiency (MIM 103850), and muscle pyruvate kinase deficiency. All these disorders are extremely rare conditions. The latter five represent muscle glycogenoses with a defect in glycolysis and cause symptoms and signs similar to type V glycogen storage disease.

Hepatic glycogenosis with renal Fanconi Syndrome is now known to be caused by defects in the facilitative glucose transporter 2 (GLUT2), which transports glucose in and out of hepatocytes, pancreatic beta cells and the basolateral membranes of intestinal and renal epithelial cells.

Sign in to your MyAccess profile while you are actively authenticated on this site via your institution (you will be able to verify this by looking at the top right corner of the screen - if you see your institution's name, you are authenticated). Once logged in to your MyAccess profile, you will be able to access your institution's subscription for 90 days from any location. You must be logged in while authenticated at least once every 90 days to maintain this remote access.

Ok

## Subscription Options

### OMMBID Full Site: One-Year Subscription

Connect to the full suite of OMMBID content including new and revised chapters that reflect the latest research, image galleries, clinical phenotypes, and more.