Robert M. Issenman

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

Cyclic vomiting syndrome in adults

Abstract  Cyclic vomiting syndrome (CVS) was initially described in children but can occur in all age groups. Cyclic vomiting syndrome is increasingly recognized in adults. However, the lack of awareness of CVS in adults has led to small numbers of diagnosed patients and a paucity of published data on the causes, diagnosis and management of CVS in adults. This article is a state‐of‐knowledge overview on CVS in adults and is intended to provide a framework for management and further investigations into CVS in adults.

Positron emission tomography in the investigation of pediatric inflammatory bowel disease

Background: Endoscopic and radiologic studies are frequently required in inflammatory bowel disease (IBD) to determine disease activity, extent of disease, and delineating disease type. Positron emission tomography (PET) using fluorine‐18‐fluoro‐deoxyglucose to identify metabolically active tissues may offer a simple noninvasive alternative to conventional studies in identification and localization of active intestinal inflammation in children with IBD. The aim of this study was to assess the value of PET in identifying active intestinal inflammation compared with conventional endoscopic and radiologic studies, including small bowel follow‐through and colonoscopy. Methods: Sixty‐five children were enrolled in the study. This included 55 children (mean age, 13.3 yr; range, 7‐18 yr; 20 girls) with newly diagnosed IBD (37) or symptoms suggestive of recurrent disease (18) and 10 children with recurrent abdominal pain (mean age, 12.7 yr; range, 8‐15 yr; 7 girls) who were studied with PET, and the results were compared with small bowel follow‐through with pneumocolon and/or colonoscopy. Thirty‐eight patients had Crohns disease (17 ileal, 12 ileocolic, 5 pancolonic, 3 left‐sided disease, 1 right‐sided disease), and 17 had ulcerative colitis (15 pan‐colitis, 2 left‐sided colitis). Mean time interval between PET and other studies was 30 ± 17.6 days. Results: PET correctly identified active inflammatory disease in 80% of children with IBD (81.5% with Crohns disease; 76.4% with ulcerative colitis) and correctly showed no evidence of inflammation in children with recurrent abdominal pain. Gluorine‐18‐fluoro‐deoxyglucose accumulated at sites that corresponded with active disease at colonoscopy in 83.8% of patients and with small bowel follow‐through with pneumocolon 75.0% of the time. Conclusion: This study suggests that PET offers a noninvasive tool for identifying and localizing active intestinal inflammation in children with IBD. PET may not be able to replace conventional studies; however, it may be useful when conventional studies cannot be performed or fail to be completed.

Clinical efficacy of probiotics: review of the evidence with focus on children.

Probiotics are marketed in several countries and widely used by pediatric health care providers. Although probiotics can be helpful for specific disorders, they have been broadly prescribed for disorders without clear evidence to support their use. Furthermore, in certain specific conditions, probiotics cause clinical deterioration. This report is a review and evaluation of the evidence or lack thereof to support a beneficial effect of probiotic agents in a variety of pediatric conditions and to review the safety and potential adverse events that may be encountered when using probiotics. It is also important to emphasize that probiotics are highly heterogeneous with differences in composition, biological activity, and dose among the different probiotic preparations.

Chronic recurrent multifocal osteomyelitis associated with chronic inflammatory bowel disease in children.

Chronic recurrent multifocal osteomyelitis(CRMO) is a rare disease of children characterized byaseptic inflammation of the long bones and clavicles. Noinfectious etiology has been identified, and CRMO has been associated with a number of autoimmunediseases (including Wegeners granulomatosis andpsoriasis). The relationship between CRMO andinflammatory bowel disease is poorly described. Throughan internet bulletin board subscribed to by 500pediatric gastroenterologists, we identified sixinflammatory bowel disease patients (two with ulcerativecolitis, four with Crohns colitis) with confirmed CRMO. In all cases, onset of the bony lesionspreceded the onset of bowel symptoms by as much as fiveyears. Immunosuppressive therapy for the bowel diseasegenerally resulted in improvement of the bone inflammation. Chronic recurrrent multifocalosteomyelitis should be considered in any inflammatorybowel disease patient with unexplained bone pain orareas of uptake on bone scan. CRMO may be a rareextraintestinal manifestation of inflammatory bowel disease;alternatively, certain individuals may be geneticallypredisposed to the development of bothdiseases.

Longitudinal assessment of growth, mineral metabolism, and bone mass in pediatric Crohn's disease.

Summary In children with inflammatory bowel disease, controversy continues about the use of long-term alternate day prednisone therapy (ADP) to suppress disease activity and to encourage appetite and growth. One possible side effect of both disease process and prednisone therapy is risk of development of osteoporosis. To evaluate this risk factor, growth, biochemical indices of mineral and vitamin D status, and bone mass were measured in nine adolescents with Crohns disease (CD) who were treated with ADP (0.3 mg/kg >3 months per year) compared with eight adolescents treated with minimal ADP exposure (<3 months per year). Single photon densitometry was used to measure bone mineral mass at the 1/3 distal radius three times over 2 years. Mean age of the 17 CD boys was 13.9 ± 2.1 years at baseline. CD patients had lower bone BMC/BW mineral content/bone width (BMC/BW) compared with age- and height-matched normal boys at all times. The difference was less when compared to height-matched normal values as CD patients were shorter than healthy reference boys. Plasma 1,25-dihydroxyvitamin D, alkaline phosphatase, and parathyroid hormone significantly increased with treatment of disease but there were no differences between treatment groups. CD patients treated with ADP had similar heights and weights at baseline and demonstrated similar linear growth over 2 years (9.1 cm/2 years) to CD patients without ADP (10.3 cm/2 years). In both groups, BMC/BW increased significiantly from year 1 to year 2, but absolute values for bone mass did not differ between the groups. These data suggest that over a 2-year treatment period male CD patients with chronic low-dose ADP exposure achieve linear growth rates and maintain bone mineralization at least as well as male CD patients who do not receive ADP.

Evaluation of neurocardiac signals in pediatric patients with cyclic vomiting syndrome through power spectral analysis of heart rate variability

OBJECTIVE To investigate autonomic regulation of neurocardiac signals in pediatric patients with cyclic vomiting syndrome (CVS). METHODS Fourteen patients with CVS, ages 3 to 16 years, were screened to eliminate any underlying cause for their symptoms, although 11 of the 14 patients had a history of migraine in the immediate family. Analysis of autonomic regulation was accomplished through power spectral analysis of the beat-to-beat heart rate variability signal. Data from affected patients were compared with data from 38 control subjects, ages 5 to 16 years, by a one-way analysis of variance. A measure of sympathovagal balance was obtained by computing a ratio of power in the low-frequency band (0. 02-0.15 Hz) to the power in the high-frequency band (0.15-0.4 Hz). RESULTS Pediatric patients with CVS have an elevated sympathetic modulation of the sinus node as represented by the low frequency/high frequency ratio (1.45 +/- 0.42 in patients vs 0.89 +/- 0.29 in healthy control subjects, P <.001). CONCLUSIONS The patients with CVS we studied have an autonomic imbalance with enhanced sympathetic and diminished parasympathetic vagal modulation of the heart.

Nutrition support for pediatric patients with inflammatory bowel disease: a clinical report of the North American Society for Pediatric Gastroenterology, Hepatology And Nutrition.

Impairment of growth and malnutrition are significant complications of inflammatory bowel disease (IBD) in pediatric patients. Since this topic was last reviewed in these pages (), a number of studies have further explored the epidemiology and pathogenesis of these nutritional complications of IBD in an effort to provide more effective interventions to prevent the long-term consequences of chronic nutrient deficiencies in childhood. In addition, during the past 15 years, the use of selected nutrients and microorganisms (probiotics) as primary or adjunctive therapy for the treatment of IBD has become an emerging area of great interest. The following is a Clinical Report from the Nutrition and Inflammatory Bowel Disease Committees of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.

Well-adjusted children: An alternate view of children with inflammatory bowel disease and functional gastrointestinal complaints

Summary: Previous studies have suggested impaired psychosocial adjustment in children and adolescents with inflammatory bowel disease (IBD). We examined 62 subjects referred to a regional Pediatric Gastroenterology Clinic with IBD or functional gastrointestinal (FGI) complaints. Characteristics of the clinic include a unified team approach, regularly scheduled appointments at 3‐month intervals, proactive medical care emphasizing maintenance of full functioning, and close medicalsurgical interaction (joint clinics). A research assistant administered a questionnaire regarding childrens perceptions of their illness, as well as the Child Depression Inventory (CDI), the Piers‐Harris (PH) test of self‐concept, and the Child Behaviour Checklist (CBCL). The 36 children with IBD (25 Crohns disease, 11 ulcerative colitis, mean age 13.3 ± 3.0 years) were compared with 26 patients with FGI complaints (16 recurrent abdominal pain, 10 functional megacolon, mean age 11.4 ± 2.8 years). The scores on the standardized tests were not clinically significant for either group. In comparison, however, children with IBD were less depressed and had fewer behaviour problems than the FGI group. Surprisingly, only 19% (7 of 36) of children with IBD described their illness as a problem to them, compared with 65% (17 of 26) of children with FGI symptoms. The latter children also considered themselves significantly sicker than did those with IBD. We conclude that normal psychosocial adjustment is possible in pediatric patients with IBD. We speculate that this group benefitted from the professional supports that our clinic specifically provides to patients with IBD. The FGI group may have suffered from a lack of such professional supports, as well as from the absence of a specific diagnosis.

Lumbar spine bone mineral density at diagnosis and during follow-up in children with IBD.

Lumbar spine body mineral density (BMD) was measured in 123 children (65 male, 58 female) suffering from inflammatory bowel disease (IBD) (82 Crohns disease, 41 ulcerative colitis) and in 46 children (25 male, 21 female) without any history of bone disease. Results in normal children showed that densitometer-derived reference values overestimated spine BMD, particularly for young children, such that the reported mean Z-scores for normal 10-yr-old children were -0.83 for males and -0.72 for females. For children with Crohns disease, the lumbar spine BMD was further reduced (Z-score = -1.44 for males, Z-score = -1.37 for females). For children with ulcerative colitis, the lumbar spine BMD was similar to that of normal children (Z-score = -0.93 for males, Z-score = -0.56 for females). There was no statistically significant reduction in average spine BMD Z-scores during follow-up periods ranging from 1.7 to 8.7 yr. When growth patterns were examined in individual children, six patients (three Crohns disease, three ulcerative colitis) were identified as losing spine BMD with respect to their baseline value and their expected pattern of BMD increase associated with normal growth. The children suffering from IBD who, most likely, will not maintain expected growth-related increases in spine BMD are those who are male, relatively young at diagnosis, and unlikely to be taking immunosuppressants.