GLYCOGEN
GLYCOGEN, THE STORAGE FORM OF GLUCOSE IN ANIMAL CELLS, IS COMPOSED OF
GLUCOSE RESIDUES JOINED IN STRAIGHT CHAINS BY A 1 -4 LINKAGES AND BRANCHED AT INTERVALS OF 4 TO 10 RESIDUES WITH A 1 -6 LINKAGES. THE TREELIKE MOLECULE CAN HAVE A MOLECULAR WEIGHT OF MANY MILLIONS AND MAY AGGREGATE TO FORM STRUCTURES RECOGNIZABLE BY ELECTRON MICROSCOPY. IN MUSCLE, GLYCOGEN FORMS P PARTICLES, WHICH ARE SPHERICAL AND CONTAIN UP TO 60,000 GLUCOSE RESIDUES. EACH P PARTICLE CONTAINS A COVALENTLY LINKED PROTEIN CALLED GLYCOGENIN. LIVER CONTAINS P PARTICLES AND ROSETTES OF GLYCOGEN CALLED A PARTICLES, WHICH APPEAR TO BE AGGREGATED 3 PARTICLES.
THE PRIMARY FUNCTION OF GLYCOGEN VARIES IN DIFFERENT TISSUES. IN
SKELETAL MUSCLE, STORED GLYCOGEN IS A SOURCE OF FUEL THAT IS USED FOR
SHORT-TERM, HIGH-ENERGY CONSUMPTION DURING MUSCLE ACTIVITY: IN THE
BRAIN, THE SMALL AMOUNT OF STORED GLYCOGEN IS USED DURING BRIEF PERIODS
OF HYPOGLYCEMIA OR HYPOXIA AS AN EMERGENCY SUPPLY OF ENERGY. IN
CONTRAST, THE LIVER TAKES UP GLUCOSE FROM THE BLOODSTREAM AFTER A MEAL
AND STORES IT AS GLYCOGEN. WHEN BLOOD GLUCOSE LEVELS START TO FALL, THE
LIVER CONVERTS GLYCOGEN BACK INTO GLUCOSE AND RELEASES IT INTO THE BLOOD FOR USE BY TISSUES SUCH AS BRAIN AND ERYTHROCYTES THAT CANNOT STORE SIGNIFICANT AMOUNTS OF GLYCOGEN.
GLYCOGEN STORAGE DISEASES ARE INHERITED DISORDERS THAT AFFECT GLYCO-
GEN METABOLISM. DISORDERS IN VIRTUALLY EVERY ENZYME INVOLVED IN THE
SYNTHESIS OR DEGRADATION OF GLYCOGEN AND ITS REGULATION CAUSE SOME
TYPE OF GLYCOGEN STORAGE DISEASE IN WHICH GLYCOGEN IS
ABNORMAL IN QUANTITY, QUALITY, OR BOTH. EXCLUDED FROM THIS CHAPTER ARE
THOSE CONDITIONS IN WHICH TISSUE GLYCOGEN ACCUMULATION IS SECONDARY,
SUCH AS OVER TREATMENT OF DIABETES MELLITUS WITH INSULIN OR ADMINISTRA
TION OF PHARMACOLOGIC AMOUNTS OF GLUCOCORTICOIDS.
HISTORICALLY, THE GLYCOGEN STORAGE DISEASES WERE CATEGORIZED NU-
MERICALLY IN THE ORDER IN WHICH THE ENZYMATIC DEFECTS WERE IDENTIFIED,
UP TO NUMBER VII.
BECAUSE LIVER AND MUSCLE HAVE ABUNDANT GLYCOGEN, THEY ARE THE
MOST COMMONLY AND SERIOUSLY AFFECTED TISSUES. THE HEPATIC GLYCOGEN
STORAGE DISEASES CAN BE DIVIDED INTO TWO GROUPS, WITH SOME OVERLAP.
THE FIRST IS CHARACTERIZED BY HEPATOMEGALY AND HYPOGLYCEMIA. BECAUSE
CARBOHYDRATE METABOLISM IN THE LIVER CONTROLS PLASMA GLUCOSE LEVELS,
THE DISORDERS OF HEPATIC GLYCOGEN DEGRADATION AND GLUCOSE RELEASE
CAUSE FASTING HYPOGLYCEMIA. DISEASES IN THIS GROUP INCLUDE GLUCOSE-
6-PHOSPHATASE DEFICIENCY (TYPE 1), DEBRANCHING ENZYME DEFICIENCY
(TYPE III), LIVER PHOSPHORYLASE DEFICIENCY (TYPE VI), AND PHOSPHORYLASE
KINASE DEFICIENCY (FORMERLY TYPE VIA OR IX). THE SECOND GROUP, CHARAC-
TERIZED BY CIRRHOSIS OF THE LIVER AND HEPATOMEGALY, IS ASSOCIATED WITH
ACCUMULATION OF ABNORMAL FORMS OF GLYCOGEN, WHICH MAY BE THE CAUSE
OF THE HEPATOCELLULAR INJURY. THIS GROUP INCLUDES BRANCHING ENZYME
DEFICIENCY (TYPE IV) AND DEBRANCHING ENZYME DEFICIENCY (TYPE III).
THE ROLE OF GLYCOGEN IN MUSCLE IS TO PROVIDE SUBSTRATES FOR THE
GENERATION OF SUFFICIENT ATP FOR MUSCLE CONTRACTION. THE MUSCLE GLYCO-
GEN STORAGE DISEASES CAN ALSO BE DIVIDED INTO TWO GROUPS. THE FIRST
IS A MUSCLE-ENERGY DISORDER CHARACTERIZED BY MUSCLE PAIN, EXERCISE
INTOLERANCE, MYOGLOBINURIA, AND SUSCEPTIBILITY TO FATIGUE. THIS GROUP
INCLUDES TYPE V (MCARDLE DISEASE), A MUSCLE PHOSPHORYLASE DEFICIENCY,
AND DEFICIENCIES OF PHOSPHOFRUCTOKINASE (TYPE VII), PHOSPHOGLYCERATE
KINASE, PHOSPHOGLYCERATE MUTASE, OR LACTATE DEHYDROGENASE. SOME OF
THESE LATTER ENZYME DEFICIENCIES ARE ASSOCIATED WITH A COMPENSATED
HEMOLYSIS, SUGGESTING A MORE GENERALIZED DEFECT IN GLUCOSE METABO-
LISM. THE SECOND GROUP OF MUSCLE DISORDERS IS CHARACTERIZED BY PROGRESSIVE SKELETAL MUSCLE WEAKNESS AND ATROPHY AND/OR CARDIOMYOPATHY AND INCLUDES A LYSOSOMAL ENZYME DEFICIENCY (ACID ALPHA-GLUCOSIDASE, TYPE
II), MUSCLE DEBRANCHING ENZYME DEFICIENCY (TYPE ILIA), A FORM OF
BRANCHING ENZYME DEFICIENCY (TYPE IV), AND DEFICIENCY OF CARDIAC-
SPECIFIC PHOSPHORYLASE KINASE.
THE OVERALL FREQUENCY OF ALL FORMS OF GLYCOGEN STORAGE DISEASE IS
APPROXIMATELY I IN 20,000 TO 25,000 LIVE BIRTHS. THE MOST COMMON
CHILDHOOD DISORDERS ARE GLUCOSE-6-PHOSPHATASE DEFICIENCY (TYPE 1).
LYSOSOMAL ACID CT-GLUCOSIDASE DEFICIENCY (TYPE II), DEBRANCHER DEFI-
CIENCY (TYPE III), AND LIVER PHOSPHORYLASE KINASE DEFICIENCY (FORMERLY TYPE VIA OR IX). THE MOST COMMON ADULT DISORDER IS MYOPHOSPHORYLASE DEFICIENCY (TYPE V, OR MCARDLE DISEASE). IN THE PAST, THE PROGNOSIS FOR MANY GLYCOGEN STORAGE DISEASES WAS GUARDED. EARLY DIAGNOSIS AND BETTER MANAGEMENT HAVE IMPROVED THE SURVIVAL RATES, AND MANY AFFECTED CHILDREN ARE NOW ADULTS.