Craig A. Alter

Glycogen Storage Disease in Adults

Table 1 The glycogen storage diseases (GSD) include more than ten separate genetic defects that impair glycogen breakdown, primarily in liver or muscle or both. Even the types most frequently encountered (GSD-Ia and GSD-III) are uncommon, each with an incidence of approximately 1 in 100 000 births. Thus, no single institution has followed and reported on a large series of patients. The importance of several major complications was recognized only recently because only single cases were initially reported. Our study represents the largest number of adults with GSD-Ia and GSD-Ib to be included in one investigation and is the first to focus on clinical and social outcomes. Although two groups of investigators recently described the clinical course of patients with GSD in Europe and Israel, most of the patients studied were children [1, 2]. Relatively little information is available about adults with these diseases. We collected information on adults with GSD-Ia, GSD-Ib, and GSD-III in the United States and Canada in order to identify long-term complications that may be amenable to prevention and to determine the effect of the disease on education, employment, and family life. Table 1. SI Units 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 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 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 calcificati

Short- and long-term use of octreotide in the treatment of congenital hyperinsulinism

Octreotide, a long-acting analog of somatostatin that inhibits insulin release, has the potential to control hypoglycemia in infants with congenital hyperinsulinism. To examine the efficacy and side effects of octreotide, we evaluated therapy between 1988 and 1993 in 16 infants who did not respond to diazoxide. In nine patients with onset of severe hypoglycemia in the first days of life, octreotide was helpful in stabilizing plasma glucose levels and allowed reductions in the rates of glucose infusion; however, glucose control was inadequate to avoid subtotal pancreatectomy. In two of these nine patients postoperatively and in seven other infants, a trial of long-term treatment with octreotide was undertaken. Four were treated successfully for up to 4.3 years. Octreotide therapy was not associated with thyroid deficiency and caused only transient malabsorption. All patients receiving long-term therapy had some decrease in linear growth and two had subnormal plasma concentrations of insulin-like growth factor I and insulin-like growth factor binding protein 3 compatible with suppression of growth hormone by octreotide. Resistance to octreotide therapy, even with increasing doses, occurred in all patients. These results suggest that octreotide may aid in the acute or long-term treatment of congenital hyperinsulinism in a limited number of selected cases.

Self-reported factors that affect glycemic control in college students with type 1 diabetes.

PURPOSE This study examined the self-reported impact of different factors on the overall diabetes care of college students with type 1 diabetes. METHODS An 18-item questionnaire was mailed to 164 students with type 1 diabetes attending college away from home; results from 42 students fulfilled study criteria and were analyzed. Metabolic control was assessed by relative changes in glycosylated hemoglobin (HbA1c) levels from medical records. RESULTS HbA1c levels did not change significantly between high school and college, yet most college students reported that diabetes was more difficult to manage in college. Commonly reported barriers to diabetes control included diet, irregular schedules, lack of parental involvement, peer pressure, drugs and alcohol, fear of hypoglycemia, and finances. Factors identified as improving diabetes control were an increased sense of responsibility, increased frequency of blood glucose testing, exercise, contact with healthcare providers, fear of hyperglycemia, and knowledge of the results of the Diabetes Control and Complications Trial. Many students reported testing their blood more frequently and taking more injections than in high school; most were on intensive insulin regimens. CONCLUSIONS Despite the perception that diabetes management was more difficult in college, metabolic control was maintained during college, possibly due to a more intensive treatment approach.

Utility of magnetic resonance imaging in the evaluation of the child with central diabetes insipidus.

Because of the association of central diabetes insipidus (CDI) and occult neoplasia, magnetic resonance imaging (MRI) is an important component of the diagnostic evaluation of a child with CDI. In more than 90% of these children, MRI (T1 weighted-image, without contrast) demonstrates an absence of the normal hyperintensity of the posterior pituitary. In one third of patients, the pituitary stalk is also thickened, suggesting infiltrative disease. Of those with a thickened stalk, the etiology of the CDI remains undetermined in about 60% of patients, whereas histiocytosis and occult germinoma each account for approximately 15-20% of patients. In contrast, germinoma is infrequent (3%) in children with CDI and an MRI showing a normal infundibular stalk, though histiocytosis still accounts for 15-20% of patients. In this paper, a diagnostic approach in children with CDI is proposed.

Subcutaneous emphysema: report of a case and review of the literature.

We report the association of subcutaneous emphysema with the use of a suprapubic bladder catheter. Review of the literature has revealed no prior reports of this complication. We have reviewed the literature on causes of tissue emphysema.

A stepwise increase in recombinant human growth hormone dosing during puberty achieves improved pubertal growth: a National Cooperative Growth Study report.

UNLABELLED The magnitude of the pubertal growth spurt contributes to adult height. Children treated with increased doses of recombinant human growth hormone (rhGH) during puberty have shown improved near adult height (NAH) outcomes that varied by treatment duration. METHODS Males, in a single clinic, treated with a prepubertal dose of rhGH (0.3 mg/kg/wk) received 0.1 mg/kg/wk dose increases with successive Tanner stages up to 0.6 mg/kg/wk. Changes in height and height SDS from pubertal onset to NAH were assessed in patients attaining NAH after > or =3 years (n = 23) and > or =4 years (n = 16). Using ANCOVA, outcomes were compared to closely matched patients (n = 758) from the National Cooperative Growth Study treated with a fixed dose (0.3 mg/kg/wk) throughout puberty. RESULTS Compared to matched patients, a 3.6 cm greater increase in mean height gain and a 0.49 greater increase in mean height SDS (p <0.0001) during puberty was observed in patients attaining NAH after > or =3 years. Corresponding values were 3.9 cm and 0.54 (p <0.0001) in patients attaining NAH after > or =4 years. CONCLUSION Stepwise increases in rhGH improved pubertal height gain when compared to a fixed dose and may represent an alternate approach to managing the patient during puberty.

Use of magnetic resonance imaging in short stature: data from National Cooperative Growth Study (NCGS) Substudy 8.

The primary use of magnetic resonance imaging (MRI) in the evaluation of children with short stature (SS) is to discover lesions in the central nervous system (CNS), particularly tumors that may require intervention. MRI has a secondary role in identifying structural abnormalities responsible for growth hormone deficiency (GHD). We examined data from the National Cooperative Growth Study (NCGS) Substudy 8 to determine how American physicians are using MRI in evaluating children with SS. Of the 21,738 short children enrolled in NCGS, 5% underwent MRI during their follow-up. Children who had GH stimulation testing were more likely to have had an MRI than those in whom no GH stimulation test was performed (19% vs 2%, p <0.0001). Moreover, children diagnosed with severe GHD (maximum GH <5 ng/ml) were more likely to have an abnormal finding on MRI. Of these patients, 27% demonstrated an abnormality as compared to 12% and 12.5% in patients with partial GHD and normal GH stimulation test results (>10 ng/ml), respectively. Abnormalities unrelated to the hypothalamus or pituitary represented 30% of these findings, while disorders in pituitary anatomy, including pituitary hypoplasia, pituitary stalk interruption, and ectopic posterior pituitary, represented an additional 30% of abnormal MRI examinations. CNS tumors comprised 23% of abnormal findings in these patients. We conclude that MRI provides significant value in the evaluation of children with SS, by identifying CNS tumors associated with growth failure as well as anatomical abnormalities of the pituitary. These findings are useful in confirming the diagnosis of GHD in children and identifying potential candidates for continued GH replacement in adulthood.

Severe Unsuspected Maternal Hypothyroidism Discovered after the Diagnosis of Thyrotropin Receptor-Blocking Antibody-Induced Congenital Hypothyroidism in the Neonate: Failure to Recognize and Implications to the Fetus

Background: Whereas most adequately treated children with congenital hypothyroidism (CH) do well neurodevelopmentally, when both the maternal and fetal thyroid glands are compromised, significant cognitive delay can occur despite early and aggressive postnatal therapy. Maternal thyrotropin-stimulating hormone receptor (TSHR)-blocking antibodies (Abs) can be transmitted to the fetus and cause combined maternal-fetal hypothyroidism. Current guidelines recommend their measurement only if mothers have known autoimmune thyroid disease, there is a history of a previously affected sibling, or when transient CH is suspected. Results: We report 3 infants in whom the diagnosis of maternal hypothyroidism was not known and was identified only after CH was diagnosed in their babies. One of these infants had developmental delay despite rapid normalization of thyroid function postnatally. All 3 mothers had potent TSHR Abs in serum, but thyroid peroxidase Abs and thyroglobulin Abs were detectable in only 2 of them. Conclusions: TSHR-blocking Ab-induced CH should be suspected in any baby with CH irrespective of the known family history, especially if the hypothyroidism is severe and a eutopic thyroid gland is demonstrated on imaging. Measurement of TSHR Abs is necessary to establish the diagnosis; the presence of other thyroid Abs is insufficiently sensitive and may miss some cases.

Glucose-6-Phosphate Dehydrogenase Deficiency Diagnosed in an Adolescent with Type 1 Diabetes Mellitus and Hemoglobin A1c Discordant with Blood Glucose Measurements

Disorders of hemolysis reduce the exposure time of hemoglobin to glucose, resulting in a falsely low hemoglobin A1c level. This case report describes the unexpected diagnosis of glucose-6-phosphate dehydrogenase deficiency made during evaluation of discordant HbA1c and blood glucose measurements.

Congenital Hyperinsulinism and Hypopituitarism Attributable to a Novel Mutation in FOXA2

Context Persistent hypoglycemia in the newborn period most commonly occurs as a result of hyperinsulinism. The phenotype of hypoketotic hypoglycemia can also result from pituitary hormone deficiencies, including growth hormone and adrenocorticotropic hormone deficiency. Forkhead box A2 (Foxa2) is a transcription factor shown in mouse models to influence insulin secretion by pancreatic β cells. In addition, Foxa2 is involved in regulation of pituitary development, and deletions of FOXA2 have been linked to panhypopituitarism. Objective To describe an infant with congenital hyperinsulinism and hypopituitarism as a result of a mutation in FOXA2 and to determine the functional impact of the identified mutation. Main Outcome Measure Difference in wild-type (WT) vs mutant Foxa2 transactivation of target genes that are critical for β cell function (ABCC8, KNCJ11, HADH) and pituitary development (GLI2, NKX2-2, SHH). Results Transactivation by mutant Foxa2 of all genes studied was substantially decreased compared with WT. Conclusions We report a mutation in FOXA2 leading to congenital hyperinsulinism and hypopituitarism and provide functional evidence of the molecular mechanism responsible for this phenotype.