Type 1 Von Gierke's disease (Cori) (glucose-6-phosphatase)
Type 2 Pompe's disease (Cori) (acid maltase)
Type 3 Smith's disease (late infantile) (acid maltase) y , y
Type 4 Engel's disease (adult) (acid maltase) y
Type 5 Forbes' disease (Cori) (debrancher- or amylo-1,6-glucosidase)
Type 6 Anderson's disease (Cori) (debrancher- or amylo-transglucosidase)
Type 7 MeArdle's disease (Cori) (myophosphorylase)
Type 8 Hers' disease (Cori) (hepatophosphorylase)
Type 9 Tarui's disease (Cori) (phosphofructokinase) y
Type 10 Hug's disease (Cori) (hepatic phosphorylase kinase) y
Type 11 Satoyoshiy's disease (phosphohexose isomerase)[42|
Type 12 Thomson's disease (phosphoglucomutase) y
Type 13 Glycogen synthase deficiency
Type 14 Bresolin's disease (phosphoglycerate kinase) y
Type 15 Tonin's disease (phosphoglycerate mutase)y
Type 16 Tsujimo's disease (laetate dehydrogenase) y
*Enzyme deficit in parenthesis.
The gene for human acid alpha-glucosidase is contained on chromosome 7q21-23. [471 Two types of mutant alleles were identified in one family in which both adults and infants had acid maltase deficiency.y One type resulted in reduced net production of active alpha-glucosidase with partial enzyme deficiency. An infant type of debrancher enzyme deficiency syndrome appears to be transmitted as an autosomal recessive trait. The heterozygous state, however, could not be diagnosed with certainty. Muscle glycogen concentrations appeared to be normal in another patient. Studies have confirmed that an autosomal recessive mode of inheritance occurred in the brancher enzyme disorder. The presence of enzymatic activity in cultured fibroblasts is lower in affected individuals than in normal controls, and the same is true (although less marked) in their parents, strongly suggesting that the trait is autosomal recessive. Tarui's disease is also transmitted in this way. Prenatal diagnosis and genetic research are indicated in further studies of these entities.
Clinical Features and Associated Disorders. In Von Gierke's disease, hypoglycemia causes many of the clinical difficulties seen in patients during the first year of life. In this period seizures are frequent, and long-standing hemiplegia and mental retardation occur. Failure to thrive, xanthomas, and isolated hepatomegaly are common, and excessive subcutaneous fat over the buttocks, breasts, and cheeks develops. Affected children usually have a protruding abdomen due to enlargement of the liver. Patients often have recurrent stomatitis frequent infections and may have isolated chronic inflammatory bowel disease.
The infant with Pompe's disease usually develops normally during the first weeks or several months of life, but hypotonia and associated weakness then occur. Spontaneous movement declines, the cry becomes weak and struggling, and swallowing is dysfunctional. Respiratory difficulty results from the skeletal muscular weakness and inability to handle pooled nasopharyngeal secretions. Massive cardiomegaly develops, and a soft, systemic murmur is often heard at the left sternal border. Ultimately, hepatomegaly appears, and the tongue may be enlarged and protrude awkwardly. Palpation of the muscles reveals them to be small and firm, and muscle stretch reflexes are suppressed. Progressive debilitation occurs, and patients usually die by 1 to 2 years of age.
In the late infantile form of acid maltase deficiency, symptoms and signs may simulate those of Duchenne's muscular dystrophy. In such patients, the gastrocnemius and deltoid muscles are firm and rubbery on palpation. There is accompanying hypertrophy of the gastrocnemius muscles, and Gowers' sign is often present. Toe walking develops with ankle contractures, and the gait is unsteady and wobbling owing to lumbar lordosis. Cardiomegaly is absent. In adults with acid maltase deficiency, weakness of the muscles develops during the third through sixth decades of life. Weakness is more prominent proximally than distally, and the pelvic girdle is involved more than the shoulders. Intercostal and diaphragmatic muscles are involved in many patients. Adults do not show enlargement of the liver, heart, or tongue. Frequently, symptoms suggesting polymyositis or late-onset muscular dystrophy cause confusion in the initial clinical diagnosis.
Three types of debrancher deficiency syndrome have
been identified: infantile, childhood, and adult. In the infantile type, early symptoms are similar to, but less marked than, those typical of Von Gierke's disease, which is associated with hypoglycemia, failure to thrive, and hepatomegaly. Patients with the infantile type are hypotonic and weak and have poor head control. Juvenile-onset debrancher enzyme deficiency begins between the ages of 2 and 15 with exercise intolerance and associated heart failure. These patients are hypotonic and have a protuberant abdomen. Adult patients develop progressive chronic myopathy in middle age.
Clinical manifestations of the infantile brancher deficiency syndrome are generally seen in the first 6 months of life and are related to failure to thrive, hepatosplenomegaly, and frank liver failure with cirrhosis. Such patients have poor motor and mental development, muscular hypotonia, and weakness. Muscle atrophy appears early and is accompanied by hyporeflexia. More benign forms of this variant present later in life with only mild hepatomegaly and elevated liver enzymes.
Children affected with classic McArdle's disease (myophosphorylase deficiency) initially show decreased stamina and easy fatigability. Although onset usually occurs in childhood, neonatal presentations have been reported. Severe cramping pain, usually in the distal skeletal muscles, develops after exercise and is often associated with renal impairment. In adolescence and adulthood, patients may develop persistent weakness and moderate loss of muscle bulk. Patients with Hers' disease have no specific neurological or muscle findings but display varying degrees of growth retardation, hypoglycemia, ketosis, and hepatomegaly. In Tarui's disease, motor development is normal during the first decade, but decreased muscle exercise tolerance, myoglobulinuria, and easy fatigability develop in childhood. An unusual infantile syndrome characterized by limb weakness, seizures, cortical blindness, and corneal opacifications occurs; microscopic studies reveal typical findings of neuron axonal dystrophy.y
Mild cases of hepatophosphokinase deficiency (Hug's disease) have been associated with hepatomegaly, attacks of ketonuria with fasting, and intermittent diarrhea. Involvement of muscle with accompanying weakness is reported.
Those with Satoyoshi's disease experience muscle pain and stiffness with exercise. Exercise tolerance is present in childhood with some muscle pain, but the symptoms become more prominent later in life. Muscle contractures do not occur after ischemic exercise.
Numerous episodes of supraventricular tachycardia occurred in an infant with Thomson's disease. The baby developed normally until he was about 18 months old, when he began to walk on his toes. Examination revealed mild weakness and poor muscle development. Calf muscles were bulky and firm, and the Achilles' tendons were shortened. There was no clinical history of exercise intolerance, muscle pain, or myoglobinuria. Yet another patient had recurrent vomiting, lethargy, and poor weight gain. Metabolic acidosis was profound. In patients with some other glycogenosis defects, such as phosphoglycerate mutase, phosphoglycerate kinase, and lactate dehydrogenase deficiencies, a link between exercise intolerance and myoglobinuria has been found. In patients with the phosphoglycerate kinase deficiency, the defect is sex-linked, and hemolytic anemia, seizures, mental retardation, and exercise intolerance with myoglobinuria have been prominent features. In adults, phosphoglycerate mutase deficiency has been associated with myalgia, cramps, and myoglobinuria following exercise. y Lactate dehydrogenase deficiency has been reported in one patient who suffered from severe myoglobinuria with exercise. In this syndrome there is a lactate dehydrogenase-M unit, which is coated on chromosome 11.
Differential Diagnosis. Most of the glycogen storage disorders must be differentiated from various myopathies and muscular dystrophies. In the former, abnormalities are seldom limited to the muscle. Liver failure problems and other systemic symptoms are often obvious. Because of the liver problems present in most of these diseases, one must always consider other storage diseases such as the mucopolysaccharidoses, mucolipidoses, sphingomyelinoses, cere- brosidoses, and gangliosidoses in the differential diagnosis.
Evaluation. These diagnoses can usually be made by performing assays of enzymatic activity in the particular tissue most affected, such as the liver, peripheral white cells, muscle, and even brain. Since severe hypoglycemia is the best screening indicator of this class of disease, postprandial and glucose tolerance tests are particularly useful. A variety of other biochemical tests, such as uric acid, cholesterol, fatty acids, triglycerides, lipid profiles, and liver function tests, should be performed, as well as bone studies in specific instances.
Management, Prognosis, and Future Perspectives. Therapy varies depending on the particular syndrome involved. In Von Gierke's disease, small amounts of free glucose can be given to maintain normal glucose concentrations; dietary carbohydrates are also given, but because excessive glucose leads to glycogen storage in the liver and kidneys, small feedings of carbohydrates are the preferred method of treatment. Dietary substitution of medium- chain for long-chain triglycerides has been used, and diazoxide has been beneficial in some cases. Portal caval shunts have been used to bypass the liver. Preoperative intravenous hyperalimentation appears to eliminate some of the metabolic problems that occur following surgery. Liver transplantation has been performed with apparent beneficial results. No practical treatment is available for Pompe's disease. Epinephrine administration has reduced liver glycogen content to normal but not that in muscle. In patients with the late infantile form, muscle glycogen content has been diminished. y
Special preparations of amyloglucosidase from Aspergillus foetidus have reduced striated muscle glycogen content, lengthened the PR interval, and decreased ventricular electrical forces. Intravenous administration of deficient enzyme to mice results in uptake into skeletal muscle. y
In the debrancher syndromes, growth failure and hepatic dysfunction, including hypoglycemia, appear to improve with the administration of oral cornstarch. Treatment with a combination of zinc, glucagon, and alpha-glucosidase reduced liver glycogen concentrations in an infant, although the infant died at 11 months of age from an infection.y Orthoptic liver transplantation has been attempted with varying success.
A fat-rich diet in patients with McArdle's disease has
shortened the muscle recovery period from an acute physical load. Maximum strength does not appear to be improved by the fat-rich diet, but tolerance for submaximal loads appears to be increased, and recovery from muscle discomfort is accelerated. y Symptoms can be controlled with frequent small carbohydrate meals in Hers' disease. Despite any of these interventions, the prognosis is guarded for patients with all of the glycogenoses.
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