Bones benefit from better biochemical control in type 1 glycogen storage disease

Abstract

See related article, p 350. Fifty years ago, Gerty and Carl Cori discovered the first hepatic enzyme deficiency in man. They demonstrated that von Gierke's disease or type 1 glycogen storage disease (GSD-1) is caused by a lack of hepatic glucose-6-phosphatase (G6Pase), which catalyzes the hydrolysis of glucose-6-phosphate to glucose and inorganic phosphate.1Cori GT Cori CF. Glucose-6-phosphatase of the liver in glycogen storage disease.J Biol Chem. 1952; 199: 661-667Abstract Full Text PDF PubMed Google Scholar The production of glucose both from glycogenolysis and gluconeogenesis is impaired, resulting in severe postprandial and fasting hypoglycemia, with increased production of lactic acid, uric acid, and triglycerides. Untreated or inadequately treated patients suffer from recurrent hypoglycemia, chronic metabolic acidosis, severe failure to thrive in infancy, retarded motor development, growth failure in childhood, and delayed puberty. Treatment used to consist of frequent high carbohydrate feedings and oral bicarbonate supplements. Many children did not survive infancy; those who did were often left with severe psychomotor deficits, typically had poorly developed musculature, muscle weakness, and decreased exercise tolerance. Radiologic studies showed delayed skeletal maturation and osteopenia,2Preger L Sanders GW Gold RH Steinbach HL Pitman P. Roentgenographic skeletal changes in the glycogen storage diseases.Am J Roentgenol Radium Ther Nucl Med. 1969; 107: 840-847Crossref PubMed Scopus (12) Google Scholar, 3Miller JH Stanley P Gates GF. Radiography of glycogen storage diseases.Am J Roentgenol. 1979; 132: 379-387Crossref PubMed Scopus (21) Google Scholar and bone histopathology of autopsy specimens revealed pure osteoporosis (decreased mass of bone matrix).4Soejima K Landing BH Roe TF Swanson VL. Pathologic studies of the osteoporosis of Von Gierke's disease (glycogenosis 1a).Pediatr Pathol. 1985; 3: 307-319Crossref PubMed Scopus (17) Google Scholar In the mid-1960s and early 1970s, based on the notion that diversion of nutrient-rich portal blood would increase systemic blood glucose levels, many children with GSD-1 underwent surgery to create a portacaval shunt, with dubious long-term benefit.5Starzl TE Putnam CW Porter KA Halgrimson CG Corman J Brown BI et al.Portal diversion for the treatment of glycogen storage disease in humans.Ann Surg. 1973; 178: 525-539Crossref PubMed Scopus (84) Google Scholar Understanding of the pathophysiologic features of the disease and its complications has progressed considerably.6Wolfsdorf JI Holm IA Weinstein DA. Glycogen storage diseases. Phenotypic, genetic, and biochemical characteristics, and therapy.Endocrinol Metab Clin North Am. 1999; 28: 801-823Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar The era of modern management of GSD-1 commenced soon after the seminal observation that 2 to 3 weeks of intravenous hyperalimentation maintained normoglycemia, corrected acidosis and hyperlipidemia, reduced liver size, and improved nutritional status in two severely afflicted children.7Folkman J Phillipart A Tze W-J Crigler JF. Portacaval shunt for glycogen storage disease: value of prolonged intravenous hyperalimentation before surgery.Surgery. 1972; 72: 306-314PubMed Google Scholar When an appropriate amount of dietary glucose (together with other essential nutrients) is provided throughout the day and night, hypoglycemia is prevented, the biochemical abnormalities are ameliorated, and growth improves.8Greene HL Slonim AE O’Neill Jr, JA Burr IM Moran JR. Type 1 glycogen storage disease: five years of management with nocturnal intragastric feeding.J Pediatr. 1980; 96: 590-595Abstract Full Text PDF PubMed Scopus (54) Google Scholar, 9Smit GPA. The long-term outcome of patients with glycogen storage disease type Ia.Eur J Pediatr. 1993; 152: S52-S55Crossref PubMed Scopus (39) Google Scholar, 10Wolfsdorf JI Crigler Jr., JF Effect of continuous glucose therapy begun in infancy on the long-term clinical course of patients with type I glycogen storage disease.J Pediatr Gastroenterol Nutr. 1999; 29: 136-143Crossref PubMed Scopus (48) Google Scholar It is now clear that many of the metabolic abnormalities of GSD-1 are the consequence of the hormonal response to hypoglycemia, which is characterized by insulinopenia and increased circulating levels of counterregulatory hormones.11Greene HL Slonim AE Burr IM. Type 1 glycogen storage disease: a metabolic basis for advances in treatment.Adv Pediatr. 1979; 26: 63-92PubMed Google Scholar, 12Wolfsdorf JI Rudlin CR Crigler Jr., JF Physical growth and development of children with type 1 glycogen-storage disease: comparison of the effects of long-term use of dextrose and uncooked cornstarch.Am J Clin Nutr. 1990; 52: 1051-1057PubMed Scopus (26) Google Scholar In the untreated state, whole body protein synthesis is significantly reduced, but improves when adequate glucose is provided through nasogastric feedings.13Yudkoff M Nissim I Stanley C Baker L Segal S. Glycogen storage disease: effects of glucose infusions on [15N] glycine kinetics and nitrogen metabolism.J Pediatr Gastroenterol Nutr. 1984; 3: 81-88Crossref PubMed Scopus (7) Google Scholar Long-term studies show that when continuous glucose therapy is started in early infancy, before severe growth failure has occurred, mean height Z score is within one SD of target or midparental height and within the normal range for the population.10Wolfsdorf JI Crigler Jr., JF Effect of continuous glucose therapy begun in infancy on the long-term clinical course of patients with type I glycogen storage disease.J Pediatr Gastroenterol Nutr. 1999; 29: 136-143Crossref PubMed Scopus (48) Google Scholar, 14Weinstein D Wolfsdorf JI. Effect of continuous glucose therapy with uncooked cornstarch on the long-term clinical course of type 1a glycogen storage disease.Eur J Pediatr. 2002; (in press)PubMed Google Scholar Bone mineral accretion occurs steadily throughout childhood, accelerates during puberty, and continues into the third decade of life. Diet (protein, calcium, vitamin D), weight-bearing physical activity, and puberty all have important effects on bone mineralization and bone health in children and adolescents.15Bachrach LK. Acquisition of optimal bone mass in childhood and adolescence.Trends Endocrinol Metab. 2001; 12: 22-28Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar, 16Leonard MB Zemel BS. Current concepts in pediatric bone disease.Pediatr Clin North Am. 2002; 49: 143-173Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar Mechanical stimulation of bone through physical activity is especially important in promoting normal bone accretion throughout this period.17Burr DB. Muscle strength, bone mass, and age-related bone loss.J Bone Miner Res. 1997; 12: 1547-1551Crossref PubMed Scopus (424) Google Scholar Disturbances in many of these factors as a result of inadequate therapy could account for decreased bone mineralization in GSD-1. Patients with GSD-1b are at an even greater risk of bone demineralization because, in addition to a deficiency of G6Pase activity, they have neutropenia and functional impairments of circulating neutrophils and monocytes, are prone to recurrent bacterial infections, and frequently have inflammatory bowel disease and intestinal malabsorption.18Visser G Rake JP Fernandes J Labrune P Leonard JV Moses S et al.Neutropenia, neutrophil dysfunction, and inflammatory bowel disease in glycogen storage disease type Ib: results of the European Study on Glycogen Storage Disease type I.J Pediatr. 2000; 137: 187-191Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar In this issue of The Journal of Pediatrics , Schwahn et al19Schwahn B Rauch F Wendel U Schönau E. Low bone mass in glycogen storage disease type 1 is associated with reduced muscle force and poor metabolic control.J Pediatr. 2002; 141: 350-356Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar provide cross-sectional data on muscle force, bone mass and density measured by peripheral quantitative computerized tomography, and metabolic control in children and adolescents with GSD-1a and -1b. Distal radius bone mass and maximal isometric grip force, a measure of muscle strength, were significantly reduced in the group as a whole, mainly owing to low values in subjects with chronically poor metabolic control. In most of the subjects, bone mass was adequately adapted to the mechanical requirements imposed by muscle contraction. There were no consistent abnormalities in serum calcium, phosphorus, vitamin D or parathyroid hormone levels or in markers of bone metabolism. A number of patients had hypercalciuria. This study shows that low bone mass in GSD-1 can be caused by both reduced muscle strength (most likely a consequence of poor metabolic control of the disease) and a direct effect of the disease. The latter could possibly be a consequence of chronic lactic acidosis. Even patients with relatively well-controlled GSD-1 typically have modestly increased blood lactate concentrations and, although venous blood pH is within the normal range, blood total carbon dioxide content tends to be at the low end of the normal range.10Wolfsdorf JI Crigler Jr., JF Effect of continuous glucose therapy begun in infancy on the long-term clinical course of patients with type I glycogen storage disease.J Pediatr Gastroenterol Nutr. 1999; 29: 136-143Crossref PubMed Scopus (48) Google Scholar Bone may have an important role in buffering long-term acid loads. It contains a large reservoir of alkaline salts that could potentially be mobilized and has sites on its surface that are potentially available to buffer hydrogen ions. As a consequence of protecting extracellular bicarbonate levels, mineral may be lost from bone with increased urinary calcium and phosphorus excretion.20Kraut JA Coburn JW. Bone, acid, and osteoporosis.N Engl J Med. 1994; 330: 1821-1822Crossref PubMed Scopus (32) Google Scholar The cornerstone of modern management of GSD-1 is to provide a continuous supply of glucose throughout the day and night to maintain the plasma glucose concentration above the threshold (~70 mg/dL) for activation of glucose counterregulatory mechanisms and blood lactic acid concentrations of near to normal. Since hepatic G6Pase is required to convert galactose to glucose, patients with GSD-1 are obliged to avoid foods that contain galactose; consequently, their diets are usually devoid of dairy products. Optimal nutritional management must, therefore, also ensure the provision of adequate amounts of supplemental calcium and vitamin D. Schwahn et al19Schwahn B Rauch F Wendel U Schönau E. Low bone mass in glycogen storage disease type 1 is associated with reduced muscle force and poor metabolic control.J Pediatr. 2002; 141: 350-356Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar have shown that meticulous dietary treatment and strict adherence to the regimen can assure normal or nearly normal physical growth and musculoskeletal development. Today, children with GSD-1 should have the physical strength and vitality to participate in physical activities with their peers, and the specter of a severely growth retarded child with wasted musculature, massive hepatomegaly, and a protuberant abdomen should now only be seen in old medical textbooks. Low bone mass in glycogen storage disease type 1 is associated with reduced muscle force and poor metabolic controlThe Journal of PediatricsVol. 141Issue 3PreviewObjective: To study the relation between muscle force, bone mass, and metabolic control in patients with glycogen storage disease type (GSD 1). Study design: Distal radius bone mass and density were evaluated in 19 patients with GSD 1 (15 GSD 1a, 4 GSD 1b) by means of peripheral quantitative computed tomography. Grip force was quantified with a dynamometer. Results: Height, weight, bone mass, and grip force were significantly decreased in the patients with GSD 1a, mainly as the result of low values in the poorly controlled subgroup. Full-Text PDF