Glycogen Storage Disease Types Ia, Ib, and III

Glycogen storage disease type Ia results from deficient glucose-6-phosphatase activity in liver, kidney, and intestine [3]. Glucose-6-phosphatase is a single 35-kd protein [4]. When glucose-6-phosphatase activity is deficient, the liver is unable to hydrolyze glucose from glucose-6-phosphate that has been derived either from the metabolism of stored glycogen or from gluconeogenesis. Patients must depend on dietary carbohydrate to maintain euglycemia; during a fast of more than a few hours, the serum glucose concentration may decrease profoundly, and seizures are common in children. Mental retardation is uncommon, however, because the brain is protected by its ability to metabolize lactate that is present at high concentrations in the serum. Chronic hypoglycemia causes a sustained increase of counter-regulatory hormones, such as cortisol. In childhood, GSD-Ia typically results in poor growth and delayed puberty. Hyperuricemia occurs probably because ATP synthesis from ADP is driven by deamination of the AMP product to inosine that is subsequently metabolized to uric acid. Renal excretion of uric acid may also be decreased because lactate competes for the renal anion transporter. Fatty liver and hyperlipidemia result from the large influx of adipose-derived fatty acids into the liver in response to low insulin and high glucagon and cortisol concentrations. Anemia that is refractory to iron supplementation is believed to occur because of chronic disease. In untreated adults with GSD-Ia, the blood glucose decreases only to about 2.8 mmol/L (50 mg/dL) after an overnight fast. Symptomatic hypoglycemia is uncommon in untreated adults, but increases of counter-regulatory hormones probably persist. Adults with GSD-Ia have a high incidence of hepatic adenomas and focal segmental glomerulosclerosis [3, 5, 6]. The continuing abnormalities in counter-regulatory hormones, together with the hyperuricemia and hyperlipidemia, may be responsible for many of the complications observed in adult patients.

Glycogen storage disease type Ib results from a deficiency of the glucose-6-phosphate translocase that transports glucose-6-phosphate into the lumen of the endoplasmic reticulum where it is hydrolyzed by glucose-6-phosphatase [3]. The translocase has not been purified. Without the translocase, glucose-6-phosphate cannot reach the hydrolytic enzyme; thus, patients with GSD-Ib are also unable to maintain euglycemia. The resulting metabolic consequences are identical in both forms of GSD-I. Because patients with GSD-Ib also have neutropenia and recurrent bacterial infections [3, 7], it seems likely that the glucose-6-phosphate translocase plays a role in normal neutrophil function.

In GSD-III, glycogen debranching enzyme is deficient [3]. This enzyme is a 165-kd protein that contains two catalytic sites that are required for activity. The enzyme has been cloned and sequenced [8]. Normally, successive glucose residues are released from glycogen by glycogen phosphorylase until the glycogen chains are within four glucose residues of a branch point. The first catalytic activity of the debranching enzyme (oligo-1,4,-1,4-glucantransferase) transfers three of the remaining glucose residues to the terminus of another glucose chain. The second catalytic activity (amylo-1,6-glucosidase) then hydrolyzes the branch-point glucose residue. Three molecular subgroups of GSD-III have been well defined [9]; each is associated with enzyme deficiency in the liver and with childhood hypoglycemia. In adults with GSD-III, hypoglycemia is uncommon. As in GSD-I, poor growth may be prominent, but the growth rate increases before puberty, and adult height is normal [10]. Additionally, increases in transaminase levels provide evidence of hepatocellular damage, and liver biopsies show periportal fibrosis [10], perhaps related to the abnormal short-branched glycogen structure. In patients with subtype GSD-IIIb, enzyme activity and immunoreactive material are absent in liver but are present in muscle; these patients do not have a myopathy. Patients with GSD-IIIa (78% of cases) lack enzyme activity and lack immunoreactive material in liver and muscle. Patients with GSD-IIId (7% of cases) lack only the transferase activity but have normal immunoreactive material in liver and muscle. In patients with GSD-IIIa and IIId, muscle weakness may occur either in childhood or after the third decade. Cardiomyopathy is apparent only after age 30 years [9].

Treatment of Glycogen Storage Disease

For only the past 10 to 15 years, children with GSD-Ia and GSD-Ib were treated with either intermittent uncooked cornstarch or a nocturnal glucose infusion given by intragastric tube. When euglycemia is maintained in this manner, growth and pubertal development are normal, and it is hoped that the late complications of GSD-I will be prevented. A high-protein diet was recommended for patients with GSD-III. Diet supplementation can increase the growth rate in children with GSD-III [11], but beneficial results on the myopathy have been less well documented.

In this retrospective study of adults with GSD types Ia, Ib, and III, we found, in addition to complications frequently recognized, a high incidence of osteopenia and fractures and of nephrocalcinosis, kidney stones, and pyelonephritis. We describe the long-term outlook for adult patients with GSD who have not had optimal lifelong dietary glucose therapy.

Methods

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Information on patients 18 years of age or older was obtained by contacting specialists in pediatric metabolism, endocrinology, gastroenterology, and genetics throughout the United States and Canada and by advertising through the Association for Glycogen Storage Diseases and The New England Journal of Medicine. No registries of patients with GSD are available. Information was included on living adult patients with GSD and patients who had died since 1967. Diagnosis of GSD had been confirmed by enzyme assay of each patient or of an affected sibling. Fifty-six physicians were individually contacted. Nineteen stated that they were not treating any adult patients with GSD. Thirteen physicians in private practice or at 1 of 12 medical centers filled out a detailed questionnaire or sent copies of clinic and hospital records that were reviewed by two of us. To obtain an estimate of how many patients might be missed by this survey, we reviewed records from a reference laboratory (Washington University) of 21 patients with GSD-Ia and of 21 patients with GSD-III who were diagnosed between 1955 and 1972. If still alive, these patients would now range in age from 18 to 64 years. Our study includes only 5 of these patients with GSD-I and 1 with GSD-III. Thus, this report incompletely represents North American patients with GSD who are currently older than 18 years of age.

Clinical, radiographic, and laboratory findings at the latest visit were obtained, but data were not universally available for every item on the questionnaire. In analyzing each response, information was considered to be available only if specifically recorded; omission of information was not recorded as either a negative or a positive response. The presence of liver adenomas, nephrocalcinosis, or kidney stones was based on data from ultrasound or radiographic studies. The diagnosis of osteopenia was based on data from radiographic studies.

The normal values for height were taken from the National Center for Health Statistics [12]. Normal values for serum chemistry tests [13] were used.

Results

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Glycogen Storage Disease Type Ia

Case Report

Patient 1, a 43-year-old divorced father of one child, is a poultry farmer. A liver biopsy and enzymatic assay were obtained at 4 years of age because of poor growth, hypoglycemia without seizures, hepatomegaly, and frequent nosebleeds. Despite frequent meals, growth continued to be poor, puberty was delayed, and the final adult height of 168 cm was achieved after 20 years of age. Allopurinol was taken inconsistently after one of many gouty attacks beginning from 18 years of age. The patient did not complete high school. As an adult, he has smoked 2 to 4 packs of cigarettes per day. After divorcing in his 20s, he frequently skipped breakfast and failed to follow a recommended diet. Instead, his diet was high in fat and consisted primarily of foods that required little preparation, such as candy and sandwiches. He has always denied symptomatic hypoglycemia, although his serum glucose concentration after an overnight fast is about 2.8 mmol/L (50 mg/dL).

Beginning in his mid-20s, he had recurrent episodes of flank pain and hematuria that were treated with antibiotics, and he passed kidney stones. At age 24, an intravenous pyelogram showed punctate calcifications, and at age 38, a kidney biopsy showed focal glomerulosclerosis. Ultrasound examination at age 38 showed parenchymal cysts and medullary calcifications of the kidney and multiple hepatic adenomas. Hypertension and progressive renal insufficiency developed. At age 41, creatinine clearance was 44 mL/min per 1.73 m². Chronic hemodialysis was begun at age 43, and he is waiting for a kidney transplant. His most recent laboratory test results were as follows: aspartate aminotransferase (AST), 0.25 µkatal/L (17 U/L); alanine aminotransferase (ALT), 0.25 µkatal/L (15 U/L); -glutamyltransferase, 1.62 µkatal/L (97 U/L); alkaline phosphatase, 3.5 µkatal/L (210 U/L); cholesterol, 8.22 mmol/L (318 mg/dL); triglycerides, 17.5 mmol/L (1.552 mg/dL); and uric acid, 339 µmol/L (5.7 mg/dL). His medications are allopurinol, colchicine, and iron and calcium supplements. Until his kidneys failed, he managed his own poultry farm and did heavy physical labor.

Summary of Data from Patients with Glycogen Storage Disease Type Ia

Of 37 patients with GSD-Ia for whom data were obtained, 22 were men. There were 6 sets of sibling pairs and one trio of siblings. One adult was Asian; the others were white. The mean age was 27.9 years (range, 18 to 43 years) (Figure 1). Of the 17 men for whom data were available, only 1 was above the 50th percentile in height for age 18 years (Figure 2). Four were below the 10th percentile, and another 10 were below the 5th percentile. Of 13 women, 1 was above the 50th percentile, 3 were below the 10th percentile, and 6 were below the 5th percentile. During the first 10 years of life, most of the patients were treated with frequent meals and with restriction of fructose and galactose. Seven patients received nocturnal nasogastric glucose or Vivonex (Norwich Eaton Pharmaceuticals, Inc., Norwich, New York) infusions during late childhood. Between 11 and 20 years of age, 13 patients were treated with oral uncooked cornstarch and 9 with nocturnal nasogastric infusions. Many of the patients had also received vitamin and iron supplements.

View larger version (13K): [in this window] [in a new window]   Figure 1. Distribution of patients with glycogen storage disease by age and type. Ia, Ib, and III refer to GSD types Ia, Ib, and III, respectively.

View larger version (23K): [in this window] [in a new window]   Figure 2. Heights of patients with glycogen storage disease. The area bounded by the dashed lines encompasses the 5th to the 50th percentiles for men and women [12].

Hepatomegaly was present in all 36 patients. Ultrasound examination showed that 27 of 36 (75%) patients had at least one hepatic adenoma, and 15 of these 27 patients had multiple adenomas. Fourteen of 24 (58%) patients had mildly increased serum concentrations of AST (range, 0.61 to 2.58 µkatal/L [37 to 155 U/L]), and 13 of 23 (56%) patients had increased serum ALT concentrations (range, 0.61 to 1.5 µkatal/L [37 to 90 U/L]). The serum alkaline phosphatase concentration was increased in 11 of 18 (61%) patients (range, 2.33 to 11.0 µkatal/L [140 to 662 U/L]). Thirteen of 14 (93%) patients had increased serum concentrations of -glutamyltransferase (range, 0.93 to 19 µkatal/L [56 to 1140 U/L]). Increases of the latter two enzymes are associated with cholestatic liver disease, a problem that has not been previously recognized in patients with GSD-I.

Anemia was frequent in men and women. Twenty-six of 32 (81%) patients had hemoglobin or hematocrit levels (or both) below the normal range, and anemia was recorded in 2 additional patients, although specific numerical data were not provided. In men, hemoglobin concentrations ranged from 64 to 144 g/L, with an average of 115 g/L, and hematocrits ranged from 0.222 to 0.433, with an average of 0.351. Women had hemoglobin concentrations that ranged from 80 to 129 g/L, with an average of 108 g/L, and hematocrit levels ranged from 0.274 to 0.398, with an average of 0.328.

The serum uric acid concentrations were increased in 15 of 36 patients. Uric acid values ranged from 142 to 880 µmol/L (2.4 to 14.8 mg/dL) for men, with an average value of 380 µmol/L (6.4 mg/dL). In women, uric acid concentrations ranged from 130 to 904 µmol/L (2.2 to 15.2 mg/dL), with an average of 476 µmol/L (8.0 mg/dL). Twenty-nine of the 36 patients had received or were currently receiving allopurinol. Only 4 of the patients had normal serum uric acid concentrations without treatment. Three patients had had attacks of gout.

Renal problems were common in patients with GSD-Ia. Renal calcifications or kidney stones were identified by ultrasound in 17 of 26 (65%) patients. Five patients had a history of urinary tract or kidney infections in the absence of structural abnormalities of the urinary tract. In 7 of 31 patients, the diastolic blood pressure was more than 90 mm Hg. Four of these patients, and an additional man whose blood pressure was normal, were receiving antihypertensive medications.

Urine protein or albumin content was increased in 11 of 18 (61%) patients. Six had proteinuria of between 150 and 1000 mg/d, and 5 excreted more than 1 gram of protein per day. Three additional patients had microalbuminuria. The remaining patients had trace or no proteinuria. Of the 21 patients for whom serum creatinine concentrations were available, values were normal in 20 patients. The serum creatinine level was increased in 1 man who was receiving chronic hemodialysis. The creatinine clearance was normal in 11 of 18 patients, was increased in 3, and was decreased in 4 (range, <10 to 163 mL/min).

Serum cholesterol and triglyceride concentrations were frequently increased; 25 of 33 (76%) patients had increased serum cholesterol concentrations (range, 5.22 to 14.6 mmol/L [202 to 566 mg/dL]). All 32 patients had an increased serum triglyceride concentration (range, 1.87 to 48.5 mmol/L [166 to 4298 mg/dL]). Eleven of the 32 patients had triglyceride concentrations more than 11.3 mmol/L (1000 mg/dL). Of these 11 patients, 6 were receiving cornstarch, suggesting either that the cornstarch dose or the schedule was not optimal or that maintenance of euglycemia does not invariably improve the abnormalities in synthesis or metabolism of triglyceride-rich lipoproteins [14, 15]. Treatment with gemfibrozil decreased the serum triglyceride concentration from 18.0 to 2.5 mmol/L (1596 to 223 mg/dL) in 1 patient.

In ten patients, osteonecrosis, osteopenia, or frequent fractures or all were recorded. These problems were first noted in childhood in four patients. Three adults had generalized osteopenia, and one had kyphoscoliosis. One patient had osteonecrosis as a child and had compression deformities of the eleventh and twelfth thoracic vertebrae in adulthood. Because few patients had radiologic evaluations, the true incidence of osteopenia may be even greater.

Other problems observed in the adult patients with GSD-Ia included muscle weakness, exercise intolerance or easy fatigability (8 patients), decreased libido (2 men), xanthomas (2 patients), lipomas (2 patients), hepatocellular cancer (1 patient), arthritis (1 patient), epistaxis (5 patients), pancreatitis (2 patients), symptomatic hypoglycemia (2 patients), gastroesophageal reflux with Barrett esophagus (1 patient), and depression (6 patients). One 35-year-old man had a myocardial infarction and had decreased left ventricular function diagnosed by electrocardiography and echocardiography. A 34-year-old man had pericardial fluid accumulation and had valvular problems. A 35-year-old man who died of amyloidosis-related heart failure had severe atherosclerosis in his coronary arteries.

The educational background of 31 patients was known. Five had attended school for 9 to 11 years, and 25 had completed high school. One patient, who had a seizure disorder and cognitive impairment because of hypoglycemia in infancy, completed a special high school program. Of the 20 patients with more than 12 years of education, 1 was a medical student and 19 were in college or had graduated. Four patients were neither in school nor working; employment data were not available for four different patients. The 16 employed adults were working as clerks, teachers, or independent business owners or managers. Eleven of 35 patients were married or divorced. Seven of 35 adults (5 men and 2 women) have children. No pregnancy-related problems were reported. The oldest patient was able to run marathon races through his fourth decade. Four adults died (between 1985 and 1990), two from renal failure (at 28 and 35 years of age), one from a cocaine-related myocardial infarction (at 25 years of age), and one from pneumonia (at 34 years of age).

Glycogen Storage Disease Type Ib

Case Report

Patient 2 is a 22-year-old female college junior. Glycogen storage disease type Ib was diagnosed by enzymatic assay of a liver biopsy obtained at 4 months of age because of hepatomegaly. Throughout her life she has had asymptomatic hypoglycemia if she fasted. As an infant, she became hypoglycemic (glucose level less than 1.66 mmol/L [30 mg/dL]) after a 4-hour fast. On one occasion, she had a normal neurologic examination when her blood glucose concentration was 0.22 mmol/L (4 mg/dL), and she had one grand mal seizure after a longer fast. A typical peripheral blood count was 2100 leukocytes with 10% to 15% neutrophils. Severe recurrent stomatitis, recurrent otitis media and externa, as well as perianal and perirectal abscesses were continual problems. A single episode of two brain abscesses (Staphylococcus aureus), one drained surgically and the second responding to antibiotics, occurred when she was 12 years old. Nocturnal tube feedings were instituted at 6 months of age, and continuous intragastric feedings were maintained from age 6 to 11 years. Intermittent daytime tube feedings were used when stomatitis or anorexia made it difficult for her to eat. At 18 years of age she was as tall as an 8-year-old, and no evidence of pubertal changes had occurred. At that time, and for the following 2 years, nutrients were supplied around the clock by means of an indwelling central venous line. Growth accelerated from 1.8 cm/y to 6.5 cm/y, and she entered and completed puberty during a 12-month period, with menarche occurring at 19 years of age. Her epiphyses are now closed, her height is 140 cm (interparent height: 168 cm), and her menstrual periods are regular. At age 19 years, shortly after insertion of the central venous line and before initiation of therapy using granulocyte-colony-stimulating factor (G-CSF), she developed acute fungemia (Candida albicans) with diffuse pulmonary edema (adult respiratory distress syndrome), and she recovered after a 4-week stay in an intensive care unit [16].

Radiographic osteopenia had been present since infancy, but lower extremity deformity appeared during the rapid linear growth period. The severity of the genu valgus deformity led to extensive corrective osteotomies that she had without complications while receiving prophylactic G-CSF. She became hypoglycemic (glucose level less than 2.22 mmol/L [40 mg/dL]) at the seventh hour of her most recent monitored fast. When receiving G-CSF therapy, her absolute neutrophil count is between 1500 to 2000 mm³. Stomatitis, which first appeared in infancy, was almost continuous in her late teen years. After initiation of G-CSF therapy, the stomatitis disappeared for 2 years and now is occasionally present in a milder form. Her liver edge is palpable 4 to 6 cm below the right costal margin. Her spleen, which enlarged only after G-CSF was begun, is 4 cm below the left costal margin. She has no clinical evidence of cirrhosis or renal impairment. She has mild chronic anemia unresponsive to hematinics and has a chronic mild increase in serum aminotransferase levels. She drives an automobile modified for her leg-length discrepancy and works as an administrative assistant while taking college courses. She has maintained honor roll and Dean's list grades throughout her academic career.

Summary of Data from Patients with Glycogen Storage Disease Type Ib

Data were available for 5 patients with GSD-Ib, including 2 women and 3 men. All were white, and none were siblings. The mean age was 21.8 years (range, 19 to 25 years). Of the 4 patients for whom data were available, only 1 man and 1 woman were less than the 5th percentile for height (see Figure 2). The patients with GSD-Ib were treated in childhood with nocturnal nasogastric feedings and with diets low in fructose and galactose; after 10 years of age, they had received either nocturnal nasogastric feedings or oral cornstarch treatment.

The distinguishing feature of GSD-Ib in childhood is neutropenia and frequent infections [3, 7]. Neutropenia was documented in 3 patients, but all 5 patients had had recurrent infections. Four of the patients had had gingivitis and oral ulcers, and these infections continued during adulthood in at least 3 of the patients. One woman had recurrent vulval and axillary abscesses, a perinephric abscess, an abscess involving the pectoralis muscles, and frequent upper respiratory infections; a second patient (patient 2) had had a staphylococcal brain abscess, recurrent stomatitis, and otitis media and externa. In this patient, systemic fungemia had caused the adult respiratory distress syndrome.

Two of the men with GSD-Ib had inflammatory bowel disease [17]. One of 3 patients had hepatic adenomas. Values for AST and ALT were increased in 1 of 2 patients. Serum alkaline phosphatase values were near normal in two patients. No information was available for -glutamyltransferase levels. Three patients had documented decreased hemoglobin or hematocrit values or both; the other 2 patients were said to be "anemic." Neither of the two patients for whom data were available had kidney stones. Two of 2 patients, 1 who was receiving allopurinol, had increased uric acid concentrations; the uric acid concentration was normal in a third patient, who was receiving allopurinol.

Other problems in the patients with GSD-Ib included increased triglyceride concentrations in two patients (2.0 to 3.2 mmol/L [180 and 280 mg/dL]) with normal serum cholesterol levels, hypoglycemia in adulthood (1 patient), and osteopenia or vertebral fractures or both (2 patients).

Four of the 5 patients had completed 12 years of schooling, and the fifth was in college when the data were collected. Two of the adults were unemployed, 1 worked as a pharmacology technologist, and 1 was a funeral director. None had married or had children.

Glycogen Storage Disease Type III.

Case Report

Patient 3, a 55-year-old divorced father of two children, owns and manages a small business. Type III GSD was diagnosed by liver biopsy and by enzymatic assay at 6 years of age because of hepatomegaly and a hypoglycemic seizure. He was treated with frequent meals. He had several episodes of pneumonia in childhood and was the slowest runner in his class but did not characterize himself as weak. At age 30, he had gradual onset of weakness in his hands and feet. The distal muscles atrophied, and weakness progressed to include the limb-girdle region. He fell at age 46, fracturing a vertebra, and fell again at age 47, fracturing his left hip. Subsequently, he required the use of a scooter to ambulate. During the following years, he intermittently ate a high-protein, low-fat diet. As an adult, he has smoked two packs of cigarettes per day and has overcome a drinking problem. At 55 years, he continues to manage his own business. His physical examination is normal except for a palpable liver 3 cm below the right costal margin, stasis edema of the legs to the knees, and wasting of the muscles of the shoulders, hands, feet, and calves. Dupuytren contractures are present bilaterally. His strength is decreased proximally and distally; his reflexes are 2⁺. Laboratory tests showed normal levels of electrolytes, -glutamyltransferase, creatinine, uric acid, glucose, cholesterol, triglycerides, protein, alkaline phosphatase, and iron. The AST level was 1.03 µkatal/L (62 IU/L), the ALT level was 1.25 µkatal/L (75 IU/L), and the creatine kinase level was 27.4 µkatal/L (1647 U/L) with an MB fraction of 0.88 µkatal/L (53 U/L). An electrocardiogram showed an old inferolateral infarction and showed multiple atrial premature complexes. An echocardiogram showed hypertrophic cardiomyopathy, with a small amount of resting outflow obstruction. The ultrasound examination of the liver and kidney was normal.

Summary of Data from Patients with Glycogen Storage Disease Type III

Nine patients with GSD-III, 7 men and 2 women, were studied. All were white, and none were siblings. Their mean age was 33.8 years (range, 18 to 57 years). Of the six patients (5 men, 1 woman) for whom data were available, height was greater than the 50th percentile for 5 and less than the 10th percentile for 1 (see Figure 2). At least 6 of the 9 patients had received no treatment until 20 years of age. Treatment for the other patients from birth to 20 years included a high-protein, low-fat diet. One patient took oral cornstarch briefly at 21 years of age. Two were consuming high-protein diets as adults. Hepatomegaly, which had been present in childhood in all of the patients, was present in one adult patient. No hepatic adenomas were identified in the five patients examined by ultrasound. Six of 6 patients had increased serum AST activity (range, 0.83 to 4.37 µkat/L [50 to 262 U/L]), and 6 of 6 patients had high serum ALT activity (range, 0.83 to 3.17 µkatal/L [50 to 190 U/L]). One of 2 patients had increased serum alkaline phosphatase activity, and 3 of 3 had normal serum -glutamyltransferase activity.

Two of 5 patients with GSD-III had kidney stones, and 1 of 6 had proteinuria, unrelated to kidney stones. Creatinine clearance was normal in 2 patients, increased in 1, and decreased in 1. Of 6 patients, 1 had increased serum uric acid concentrations, and another 2 were receiving allopurinol at the time the values were recorded.

Myopathy and cardiomyopathy were common in patients with GSD-III. Electrocardiograms and echocardiograms were abnormal in 4 of 6 patients; 3 had left ventricular hypertrophy, and the fourth had biventricular hypertrophy. The electrocardiograms of two of these patients showed premature atrial complexes. One patient had mild mitral regurgitation, and another had aortic insufficiency. The same four patients also had a myopathy characterized by proximal and distal atrophy and weakness. One patient used a cane for walking, and another used a scooter. The two patients whose electrocardiograms and echocardiograms were normal were not weak, although one complained of exercise intolerance. Serum creatine kinase activity was known for eight patients. Two of the patients without weakness had normal glycogen debranching enzyme activity in muscle [9]; another 2 without weakness had creatine kinase activities of 2.6 to 95.7 µkatal/L (526 and 5743 U/dL). In the three patients with severe muscle atrophy, creatine kinase activities were 27.4, 22.5, and 30.2 µkatal/L (1647, 1349, and 1812 U/dL). Two patients with weakness, but no atrophy, had values of 10.86 and 11.5 µkatal/L (652 and 689 U/dL).

Other medical problems were hypertriglyceridemia in 4 of 7 patients (1.86 to 3.4 mmol/L [165 to 302 mg/dL]), mild hypercholesterolemia in 3 of 7 patients (5.17 to 6.36 mmol/L [200 to 246 mg/dL]), and a seizure disorder in 1 patient.

The educational background of seven of the patients was known. Each had completed 12 years or more of school. Three of 6 patients had been or were currently married, and 4 patients (3 men, 1 woman) had children. One patient was unemployed, and 1 was a housewife.

Discussion

Relatively little information is available about the long-term clinical course of patients with any type of GSD. In a retrospective study, Smit and colleagues [1] included 10 patients with GSD-Ia and 12 patients with GSD-III who were older than 20 years of age. De Parscau and colleagues [2] studied 76 patients, but only a few were adults. Moses and colleagues [18] described 16 patients with GSD-III, of whom 2 were adults. Our study focused specifically on adults and describes the largest group of adult patients with GSD-Ia and GSD-Ib. The goals of our study were to identify major clinical problems in adult life and to determine the educational and employment achievements of adults with GSD. We hoped to identify potential medical problems that might be preventable. Because case finding was achieved primarily through physicians, however, our data may represent a relatively more impaired group of patients.

A report [19] in 1972 documented the correction of the biochemical abnormalities in patients with GSD-Ia when a continuous source of glucose was given at or above postprandial glucose requirements. An effective treatment using nocturnal nasogastric infusions of glucose was documented in 1976 and 1978 [20, 21]. An alternative method for providing a continuous source of glucose by using oral, uncooked cornstarch was described in 1984 [22]. Subsequently, these two methods for providing optimal therapy were compared [23-26]. Because these dietary therapies evolved during the past 20 years, many of the adults included in this retrospective study have had optimal treatment for only a portion of their lives.

Dietary treatments substantially decrease serum triglyceride and cholesterol concentrations but do not restore values to normal in most patients [14, 15]. Similarly, in the patients described in this study, serum triglyceride concentrations remained increased in all patients with GSD-I regardless of therapy. Although it is probable that not all patients were receiving optimal dietary therapy when serum lipids were measured, therapy with cornstarch or nocturnal intragastric infusion alone does not seem to be sufficient to normalize the hyperlipidemia associated with GSD-Ia. It is not known whether the hyperlipidemia of GSD-I is atherogenic; however, pancreatitis (a known complication of hypertriglyceridemia) was described in two of the patients. In addition, two men in their 30s had substantial heart problems, and severe coronary atherosclerosis was found at autopsy in a 35-year-old man. Biochemical abnormalities persist in adults with GSD-Ia and GSD-Ib who are not maintained on overnight glucose replacement therapy [27]. Such therapy, therefore, may be required to delay or prevent the complications observed even in the absence of hypoglycemic symptoms.

Many of the problems identified in our patients with GSD-Ia were similar to those described in European and Israeli patients. These included short stature, liver adenomas, increased serum AST and ALT activities, hyperuricemia, hepatomegaly, and hyperlipidemia [1, 2]. Progressive renal disease was previously well characterized [5, 6]. Although renal stones and anemia were noted [2, 6], the frequency of these problems was not generally recognized. Our finding of severe osteopenia in this group of patients is consistent with findings in a previous study [28]. The increases in alkaline phosphatase and -glutamyltransferase levels are new findings that suggest biliary tract disease or mild chronic inflammation.

Hepatic adenomas were common in patients with GSD-Ia, as previously described. Although these adenomas may be precancerous [3, 29], malignant transformation occurred in only 1 of 27 patients who had adenomas. Because maintenance of euglycemia may prevent or shrink adenomas in patients with GSD-I [30], protection may occur by continued use of cornstarch or nocturnal glucose therapy during adulthood.

Renal disease was common in patients with GSD-Ia. Proteinuria (61%) was the most frequently encountered renal complication. Creatinine clearance was frequently altered and may represent a continuum in which the first clinically demonstrable abnormality is hyperfiltration and the last is renal failure [5]. The observations made in this study agree with findings from earlier studies, which showed that nephropathy is an important complication in older patients with GSD-Ia [5, 6]. Additionally, we document, for the first time, a high prevalence of nephrocalcinosis (65%) and of pyelonephritis in the absence of structural abnormalities of the urinary tract. Serum uric acid concentrations were increased in 15 patients with GSD-I, despite treatment of 12 of these patients with allopurinol. The cause of renal failure in patients with GSD-I is not well understood, and increased serum uric acid concentrations and kidney infections could contribute to progressive renal disease. Because hyperuricemia is a risk factor for nephrocalcinosis, hyperuricemia should be treated in an effort to normalize serum uric acid levels.

Information is limited about the long-term complications specific to GSD-Ib. Our 5 patients with GSD-1b were in their 20s; the 5 patients with GSD-Ib described by Smit and colleagues [1] were less than 20 years of age, and the 4 oldest patients with GSD-Ib described by Ambruso and colleagues [7] were 18 to 21 years old. Frequent infections due to neutropenia persisted in adulthood, and gingivitis was common. The course of the infectious complications may be ameliorated by long-term administration of G-CSF [16]. None of the patients with GSD-Ib had kidney stones, and although one did have proteinuria, it is not clear from these data whether renal complications are as prominent in GSD-Ib as in GSD-Ia.

In patients with GSD-III, childhood hepatomegaly resolved with increased age, as previously described [1, 3]. Although hepatic adenomas have been described in patients with GSD-III [1, 2], none were present in our patients. Serum activities of AST and ALT were increased in patients with GSD-III, consistent with the ongoing hepatocellular damage and the fibrosis found in liver biopsy specimens [10]. The high incidence of myopathy and cardiomyopathy was similar to the incidence described in other studies that included patients of all ages [1, 9, 17, 31]. In a report [32] of 18 patients with GSD-III from 1 to 30 years old, including 5 patients more than 18 years old, cardiomyopathy was described in about one third of the patients; myopathy was described in 50%, and increased creatine kinase activities were common. Except for data on a 23-year-old woman who died from a cardiac arrhythmia, no long-term data are available on the outcome for patients who develop cardiac abnormalities when they are young [2]. Of note is the absence of renal disease, apart from kidney stones, in patients with GSD-III.

Information on schooling and employment histories showed that 86% of the adults with GSD-I and GSD-III had completed high school (32 of 37), and 23 of 30 not in school were employed at the time the data were collected. Only 1 patient was mentally handicapped. These data indicate that cognitive defects are rare in patients with GSD-I, despite their having childhood hypoglycemia, and confirm the importance of lactate as an energy source that can substitute for glucose in the brain [3]. Although only 32% of the patients with GSD had ever been married, many of the unmarried persons were still in their early 20s. Eleven of the patients have had children. Only six patients were thought to be depressed. Thus, these data indicate that although most adults with GSD have serious medical problems, their ability to complete school and to work productively is relatively unimpaired.

Several questions remain unresolved. How severe is the cardiomyopathy of patients with GSD-III? Is renal failure inevitable for patients with GSD-I in their 20s who have proteinuria or hypertension or both? Which patients with liver adenomas will develop hepatocellular carcinoma? This study and that of Smit and colleagues [1] included only six patients with GSD-I and four with GSD-III who were older than 40 years of age. Thus, the health status of patients in middle and old age remains unknown. In this study and the other large study of patients with GSD-Ia [1], 60% of the 74 patients were men. Are women who have GSD-Ia less likely to be seeing a physician or do more men survive?

Currently recommended therapy for patients with GSD-I is designed to maintain blood glucose at concentrations that prevent or minimize increased counter-regulatory hormonal activity. This therapy, which maintains near-normal biochemical variables, allows normal growth and pubertal maturation. As the cohort of patients with GSD-Ia and GSD-Ib treated with nocturnal glucose infusions or oral cornstarch, or both, enters adulthood, we can determine whether intensive dietary therapy prevents late medical complications or merely delays the complications observed in untreated adult patients.

This study indicates that renal stones, pyelonephritis, and inadequately treated hyperuricemia are common features of adults with GSD-Ia and may contribute to the progressive renal disease that is a frequent and life-threatening complication in older patients [6, 7]. Our findings suggest that physicians who care for these patients should identify and aggressively treat pyelonephritis and hyperuricemia. These data, although incomplete, suggest that osteopenia is frequent and that its cause and treatment require investigation. Osteopenia probably results from substantial counter-regulatory hormone activity caused by recurrent hypoglycemia and should be preventable by optimal glucose replacement therapy if calcium intake is adequate. Patients with GSD-Ib may require G-CSF to prevent life-threatening infections. For patients with GSD-III, an effective therapy is needed to prevent or improve the myopathy and cardiomyopathy observed when debranching enzyme activity is deficient in muscle.

Addendum

Glucose-6-phosphatase has been cloned, and several mutations have been identified that cause GSD-Ia [33].