Clinical Manifestations

Patients with type I GSD may present in the neonatal period with hypoglycemia and lactic acidosis; they more commonly present at 3-4 mo of age with hepatomegaly, hypoglycemic seizures, or both. These children often have doll-like faces with fat cheeks, relatively thin extremities, short stature, and a protuberant abdomen that is due to massive hepatomegaly; the kidneys are also enlarged, whereas the spleen and heart are normal.

The biochemical hallmarks of the disease are hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia. Hypoglycemia and lactic acidosis can develop after a short fast. Hyperuricemia is present in young children; gout rarely develops before puberty. Despite marked hepatomegaly, the liver transaminase levels are usually normal or only slightly elevated. Intermittent diarrhea may occur in GSD I. In patients with GSD Ib, the loss of mucosal barrier function due to inflammation, which is likely related to the disturbed neutrophil function, seems to be the main cause of diarrhea. Easy bruising and epistaxis are common and are associated with a prolonged bleeding time as a result of impaired platelet aggregation and adhesion.

The plasma may be “milky” in appearance as a result of a striking elevation of triglyceride levels. Cholesterol and phospholipids are also elevated, but less prominently. The lipid abnormality resembles type IV hyperlipidemia and is characterized by increased levels of very low density lipoprotein, low-density lipoprotein, and a unique apolipoprotein profile consisting of increased levels of apo B, C, and E, with relatively normal or reduced levels of apo A and D. The histologic appearance of the liver is characterized by a universal distention of hepatocytes by glycogen and fat. The lipid vacuoles are particularly large and prominent. There is little associated fibrosis.

All these findings apply to both type Ia and type Ib GSD, but type Ib has additional features of recurrent bacterial infections from neutropenia and impaired neutrophil function. Gut mucosa ulceration culminating in GSD enterocolitis is also common. Exceptional cases of type Ib without neutropenia and type Ia with neutropenia have been reported.

Although type I GSD affects mainly the liver, multiple organ systems are involved. Puberty is often delayed. Virtually all females have ultrasound findings consistent with polycystic ovaries; other features of polycystic ovary syndrome (acne, hirsuitism) are not seen. Nonetheless, fertility appears to be normal, as evidenced in several reports of successful pregnancy in women with GSD I. Increased bleeding during menstrual cycles, including life-threatening menorrhagia, has been noted and could be related to the impaired platelet aggregation. Symptoms of gout usually start around puberty from long-term hyperuricemia. Secondary to the lipid abnormalities, there is an increased risk of pancreatitis. The dyslipidemia, together with elevated erythrocyte aggregation, predisposes these patients to atherosclerosis. Premature atherosclerosis has not yet been clearly documented except for rare cases. Impaired platelet aggregation and increased antioxidative defense to prevent lipid peroxidation may function as a protective mechanism to help reduce the risk of atherosclerosis. Frequent fractures and radiographic evidence of osteopenia are common; bone mineral content is reduced even in prepubertal patients.

By the 2nd or 3rd decade of life, most patients with type I GSD exhibit hepatic adenomas that can hemorrhage and, in some cases, become malignant. Pulmonary hypertension has been seen in some long-term survivors of the disease.

Renal disease is another complication, and most patients with type I GSD who are >20 yr of age have proteinuria. Many also have hypertension, renal stones, nephrocalcinosis, and altered creatinine clearance. Glomerular hyperfiltration, increased renal plasma flow, and microalbuminuria are often found in the early stages of renal dysfunction and can occur before the onset of proteinuria. In younger patients, hyperfiltration and hyperperfusion may be the only signs of renal abnormalities. With the advancement of renal disease, focal segmental glomerulosclerosis and interstitial fibrosis become evident. In some patients, renal function has deteriorated and progressed to failure, requiring dialysis and transplantation. Other renal abnormalities include amyloidosis, a Fanconi-like syndrome, hypocitraturia, hypercalciuria, and a distal renal tubular acidification defect.

Diagnosis

The diagnosis of type I GSD is suspected on the basis of clinical presentation and the laboratory findings of hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia. Neutropenia is noted in GSD Ib patients, typically after the 1st 2-3 yr of life. Administration of glucagon or epinephrine results in little or no rise in blood glucose level, but the lactate level rises significantly. Before the glucose-6-phosphatase and glucose-6-phosphate translocase genes were cloned, a definitive diagnosis required a liver biopsy. Gene-based mutation analysis provides a noninvasive way of diagnosis for most patients with types Ia and Ib disease.

Treatment

Treatment is designed to maintain normal blood glucose levels and is achieved by continuous nasogastric infusion of glucose or oral administration of uncooked cornstarch. Nasogastric drip feeding can be introduced in early infancy from the time of diagnosis. It can consist of an elemental enteral formula or contain only glucose or a glucose polymer to provide sufficient glucose to maintain normoglycemia during the night. Frequent feedings with high-carbohydrate content are given during the day.

Uncooked cornstarch acts as a slow-release form of glucose and can be introduced at a dose of 1.6 g/kg every 4 hr for infants <2 yr of age. The response of young infants is variable. As the child grows older, the cornstarch regimen can be changed to every 6 hr at a dose of 1.75-2.5 g/kg of body weight. New starch products, which are currently being developed, are thought to be longer acting, better tolerated, and more palatable. A short-term double-blind crossover pilot study comparing uncooked, physically modified cornstarch to traditional cornstarch showed that the majority of GSD patients treated with the new starch had better short-term metabolic control and longer duration of euglycemia; however, more extensive studies replicating these results are necessary at this time. Because fructose and galactose cannot be converted directly to glucose in GSD type I, these sugars are restricted in the diet. Sucrose (table sugar, cane sugar, other ingredients), fructose (fruit, juice, high fructose corn syrup), lactose (dairy foods), and sorbitol should be avoided or limited. Due to these dietary restrictions, vitamins and minerals such as calcium and vitamin D may be deficient and supplementation is required to prevent nutritional deficiencies. Dietary therapy improves hyperuricemia, hyperlipidemia, and renal function, slowing the development of renal failure. This therapy fails, however, to normalize blood uric acid and lipid levels completely in some individuals, despite good metabolic control, especially after puberty. The control of hyperuricemia can be further augmented by the use of allopurinol, a xanthine oxidase inhibitor. The hyperlipidemia can be reduced with lipid-lowering drugs such as HMG-CoA reductase inhibitors and fibrate (Chapter 80). Microalbuminuria, an early indicator of renal dysfunction in type I disease, is treated with angiotensin-converting enzyme (ACE) inhibitors. Citrate supplements can be beneficial for patients with hypocitraturia by preventing or ameliorating nephrocalcinosis and development of urinary calculi. Growth hormone should be used with extreme caution and limited to only those with a documented growth hormone deficiency. Even in those cases, there should be close monitoring of metabolic parameters and presence of adenomas.

In patients with type Ib GSD, granulocyte and granulocyte-macrophage colony–stimulating factors are successful in correcting the neutropenia, decreasing the number and severity of bacterial infections, and improving the chronic inflammatory bowel disease.

Orthotopic liver transplantation is a potential cure of type I GSD, but the inherent short- and long-term complications leave this as a treatment of last resort, usually for patients with liver malignancy, multiple liver adenomas, metabolic derangements refractory to medical management, and/or liver failure. Large adenomas (>2 cm) that are rapidly increasing in size and/or number may require partial hepatic resection. Smaller adenomas (<2 cm) can be treated with percutaneous ethanol injection or transcatheter arterial embolization. A challenge is the recurrence of liver adenomas with potential for malignant transformation in these patients, ultimately requiring a liver transplant. Bone marrow transplantation has been reported to correct the neutropenia of type Ib.

Before any surgical procedure, the bleeding status must be evaluated and good metabolic control established. Prolonged bleeding times can be normalized by the use of intensive intravenous glucose infusion for 24-48 hr before surgery. Use of 1-deamino-8-D-arginine vasopressin (DDAVP) can reduce bleeding complications. Lactated ringer solution should be avoided because it contains lactate and no glucose. Glucose levels should be maintained in the normal range throughout surgery with the use of 10% dextrose.

Prognosis

Previously, many patients with type I GSD died at a young age, and the prognosis was guarded for those who survived. The long-term complications occur mostly in adults whose disease was not adequately treated during childhood. Early diagnosis and effective treatment have improved the outcome; renal disease and formation of hepatic adenomas with potential risk for malignant transformation remain serious complications.

Clinical Manifestations

During infancy and childhood, the disease may be indistinguishable from type I GSD, because hepatomegaly, hypoglycemia, hyperlipidemia, and growth retardation are common (Fig. 81-2). Splenomegaly may be present, but the kidneys are not enlarged. Remarkably, hepatomegaly and hepatic symptoms in most patients with type III GSD improve with age and usually resolve after puberty. Progressive liver cirrhosis and failure can occur. Hepatocellular carcinoma has also been reported, more typically in patients with progressive liver cirrhosis. The frequency of adenomas in individuals with GSD III is far less, compared to GSD I. Furthermore, the relationship of hepatic adenomas and malignancy in GSD III is unclear. A single case of malignant transformation at the site of adenomas has been noted. In patients with muscular involvement (type IIIa), muscle weakness can present in childhood but can become severe after the 3rd or 4th decade of life, as evidenced by slowly progressive weakness and wasting. Because patients with GSD III can have decreased bone density, they are at an increased risk of potential fracture. Myopathy does not follow any particular pattern of involvement; both proximal and distal muscles are involved. Electromyography reveals a widespread myopathy; nerve conduction studies are often abnormal. Ventricular hypertrophy is a frequent finding, but overt cardiac dysfunction is rare. There have been some reports of life-threatening arrhythmia and need for heart transplant in some GSD III patients. Hepatic symptoms in some patients may be so mild that the diagnosis is not made until adulthood, when the patients show symptoms and signs of neuromuscular disease. The initial diagnosis has been confused with Charcot-Marie-Tooth disease. Polycystic ovaries are common; some patients can develop hirsutism, irregular menstrual cycles, and other features of polycystic ovarian syndrome. Fertility does not appear to be reduced; successful pregnancies in patients with GSD III have been reported.

Figure 81-2 Growth and development in a patient with type IIIb glycogen storage disease. The patient has debrancher deficiency in liver but normal activity in muscle. As a child, he had hepatomegaly, hypoglycemia, and growth retardation. After puberty, he no longer had hepatomegaly or hypoglycemia, and his final adult height is normal. He had no muscle weakness or atrophy; this is in contrast to type IIIa patients, in whom a progressive myopathy is seen in adulthood.

Hypoglycemia and hyperlipidemia are common. In contrast to type I GSD, elevation of liver transaminase levels and fasting ketosis are prominent, but blood lactate and uric acid concentrations are usually normal. Serum creatine kinase levels can be useful to identify patients with muscle involvement; normal levels do not rule out muscle enzyme deficiency. The administration of glucagon 2 hr after a carbohydrate meal provokes a normal increase in blood glucose; after an overnight fast, glucagon may provoke no change in blood glucose level.

Diagnosis

The histologic appearance of the liver is characterized by a universal distention of hepatocytes by glycogen and the presence of fibrous septa. The fibrosis and the paucity of fat distinguish type III glycogenosis from type I. The fibrosis, which ranges from minimal periportal fibrosis to micronodular cirrhosis, appears in most cases to be nonprogressive. Overt cirrhosis has been seen in some patients with GSD III.

Patients with myopathy and liver symptoms have a generalized enzyme defect (type IIIa). The deficient enzyme activity can be demonstrated not only in liver and muscle, but also in other tissues such as heart, erythrocytes, and cultured fibroblasts. Patients with hepatic symptoms without clinical or laboratory evidence of myopathy have debranching enzyme deficiency only in the liver, with enzyme activity retained in the muscle (type IIIb). Definite diagnosis requires enzyme assay in liver, muscle, or both. Mutation analysis can provide a noninvasive method for diagnosis and subtype assignment in the majority of patients; however, the large size of the gene and the distribution of mutations across the entire gene present a challenge.

Treatment

Dietary management is less demanding than in type I GSD. Patients do not need to restrict dietary intake of fructose and galactose. If hypoglycemia is present, frequent meals high in carbohydrates with cornstarch supplements or nocturnal gastric drip feedings are usually effective. A high-protein diet during the daytime plus overnight protein enteral infusion can also be effective in preventing hypoglycemia and preventing endogenous protein breakdown because protein can be used as a substrate for gluconeogenesis, a pathway that is intact in type III GSD. There is no satisfactory treatment for the progressive myopathy other than recommending a high-protein diet and an exercise program. Liver transplantation has been performed in patients with end-stage cirrhosis and/or hepatic carcinoma.

Clinical Manifestations

This disorder is clinically variable. The most common and classic form is characterized by progressive cirrhosis of the liver and is manifested in the 1st 18 mo of life as hepatosplenomegaly and failure to thrive. The cirrhosis progresses to portal hypertension, ascites, esophageal varices, and liver failure that usually leads to death by 5 yr of age. Rare patients survive without progression of liver disease; these patients have a milder hepatic form and do not require a liver transplant.

A neuromuscular form of the disease has been reported; there are 4 main variants recognized based on age of presentation. The perinatal form presents as a fetal akinesia deformation sequence and death in the perinatal period. The congenital form presents at birth with severe hypotonia, muscle atrophy, and neuronal involvement with death in the neonatal period; some patients have cardiomyopathy. The childhood form presents primarily with myopathy or cardiomyopathy. The adult form presents with diffuse central and peripheral nervous system dysfunction accompanied by accumulation of polyglucosan material in the nervous system (adult polyglucosan body disease). For adult polyglucosan disease, a leukocyte or nerve biopsy is needed to establish the diagnosis because the branching enzyme deficiency is limited to those tissues.

Diagnosis

Tissue deposition of amylopectin-like materials can be demonstrated in liver, heart, muscle, skin, intestine, brain, spinal cord, and peripheral nerve. The hepatic histologic findings are characterized by micronodular cirrhosis and faintly stained basophilic inclusions in the hepatocytes. The inclusions consist of coarsely clumped, stored material that is periodic acid–Schiff positive and partially resistant to diastase digestion. Electron microscopy shows, in addition to the conventional α and β glycogen particles, accumulation of the fibrillar aggregations that are typical of amylopectin. The distinct staining properties of the cytoplasmic inclusions, as well as electron microscopic findings, could be diagnostic. However, polysaccharidoses with histologic features reminiscent of type IV disease, but without enzymatic correlation, have been observed. The definitive diagnosis rests on the demonstration of the deficient branching enzyme activity in liver, muscle, cultured skin fibroblasts, or leukocytes, or on the identification of disease-causing mutations in the glycogen branching enzyme (GBE) gene. Prenatal diagnosis is possible by measuring the enzyme activity in cultured amniocytes, chorionic villi, or mutation analysis.

Treatment

There is no specific treatment for type IV GSD. Unlike patients with the other liver GSDs (I, III, VI, IX), those with GSD IV do not have hypoglycemia, which is only seen when there is overt liver cirrhosis. Liver transplantation has been performed for patients with progressive hepatic failure, but because it is a multisystem disorder involving many organ systems, the long-term success of liver transplantation is unknown. Caution should be taken in selecting type IV patients for liver transplantation because these patients have variable phenotypes, which include a nonprogressive form of the liver disease and in some cases, extrahepatic manifestations of the disease.

Diagnosis

Definitive diagnosis of phosphorylase kinase deficiency requires demonstration of the enzymatic defect in affected tissues. Phosphorylase kinase can be measured in leukocytes and erythrocytes, but because the enzyme has many isozymes, the diagnosis can be missed without studies of liver, muscle, or heart in certain instances. Mutation analysis is necessary in many cases to determine the disease’s subtype.

The PHKA2 gene encoding the α subunit is most commonly involved, followed by the PHKB gene encoding the β subunit, regardless of the presence of deficiency in erythrocytes. Mutations in the PHKG2 gene underlying γ-subunit deficiency are typically associated with severe liver involvement with recurrent hypoglycemia and liver fibrosis.

Treatment

The treatment for liver phosphorylase kinase deficiency includes a high-carbohydrate diet and frequent feedings to prevent hypoglycemia; most patients require no specific treatment. Prognosis for the X-linked and certain autosomal forms is good. Patients with mutations in the γ subunit typically have a more severe clinical course with progressive liver disease. There is no treatment for the fatal form of isolated cardiac phosphorylase kinase deficiency other than heart transplantation.

Muscle Glycogen Synthase Deficiency

This GSD results from muscle glycogen synthase (glycogen synthase I, GYS1) deficiency.

It is extremely rare and was reported in 3 children of consanguineous parents of Syrian origin. Muscle biopsies showed lack of glycogen, predominantly oxidative fibers, and mitochondrial proliferation. Glucose tolerance was normal. Molecular study revealed a homozygous stop mutation (R462→ter) in the muscle glycogen synthase gene. The phenotype was variable in the 3 siblings and ranged from sudden cardiac arrest, muscle fatigability, hypertrophic cardiomyopathy, an abnormal heart rate, and hypotension while exercising, to mildly impaired cardiac function at rest.