A generic emergency protocol for patients with inborn errors of metabolism causing fasting intolerance: A retrospective, single-center study and the generation of www.emergencyprotocol.net.

Patients with inborn errors of metabolism causing fasting intolerance can experience acute metabolic decompensations. Long-term data on outcomes using emergency letters are lacking. This is a retrospective, observational, single-center study of the use of emergency letters based on a generic emergency protocol in patients with hepatic glycogen storage diseases (GSD) or fatty acid oxidation disorders (FAOD). Data on hospital admissions, initial laboratory results, and serious adverse events were collected. Subsequently, the website www.emergencyprotocol.net was generated in the context of the CONNECT MetabERN eHealth project following multiple meetings, protocol revisions, and translations. Representing 470 emergency protocol years, 127 hospital admissions were documented in 54/128 (42%) patients who made use of emergency letters generated based on the generic emergency protocol. Hypoglycemia (here defined as glucose concentration < 3.9 mmol/L) was reported in only 15% of hospital admissions and was uncommon in patients with ketotic GSD and patients with FAOD aged >5 years. Convulsions, coma, or death was not documented. By providing basic information, emergency letters for individual patients with hepatic GSD or the main FAOD can be generated at www.emergencyprotocol.net, in nine different languages. Generic emergency protocols are safe and easy for home management by the caregivers and the first hour in-hospital management to prevent metabolic emergencies in patients with hepatic GSD and medium-chain Acyl CoA dehydrogenase deficiency. The website www.emergencyprotocol.net is designed to support families and healthcare providers to generate personalized emergency letters for patients with hepatic GSD and the main FAOD.

Intracellular lipids are an independent cause of liver injury and chronic kidney disease in non alcoholic fatty liver disease-like context.

OBJECTIVE: Ectopic lipid accumulation in the liver and kidneys is a hallmark of metabolic diseases leading to non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD). Moreover, recent data have highlighted a strong correlation between NAFLD and CKD incidences. In this study, we use two mouse models of hepatic steatosis or CKD, each initiated independently of the other upon the suppression of glucose production specifically in the liver or kidneys, to elucidate the mechanisms underlying the development of CKD in the context of NAFLD-like pathology. METHODS: Mice with a deletion of G6pc, encoding glucose-6 phosphatase catalytic subunit, specifically in the liver (L.G6pc-/- mice) or the kidneys (K.G6pc-/- mice), were fed with either a standard diet or a high fat/high sucrose (HF/HS) diet during 9 months. These mice represent two original models of a rare metabolic disease named Glycogen Storage Disease Type Ia (GSDIa) that is characterized by both NAFLD-like pathology and CKD. Two other groups of L.G6pc-/- and K.G6pc-/- mice were fed a standard diet for 6 months and then treated with fenofibrate for 3 months. Lipid and glucose metabolisms were characterized, and NAFLD-like and CKD damages were evaluated. RESULTS: Lipid depot exacerbation upon high-calorie diet strongly accelerated hepatic and renal pathologies induced by the G6pc-deficiency. In L.G6pc-/- mice, HF/HS diet increased liver injuries, characterized by higher levels of plasmatic transaminases and increased hepatic tumor incidence. In K.G6pc-/- mice, HF/HS diet increased urinary albumin and lipocalin 2 excretion and aggravated renal fibrosis. In both cases, the worsening of NAFLD-like injuries and CKD was independent of glycogen content. Furthermore, fenofibrate, via the activation of lipid oxidation significantly decreased the hepatic or renal lipid accumulations and prevented liver or kidney damages in L.G6pc-/- and K.G6pc-/- mice, respectively. Finally, we show that L.G6pc-/- mice and K.G6pc-/- mice developed NAFLD-like pathology and CKD independently. CONCLUSIONS: This study highlights the crucial role that lipids play in the independent development of both NAFLD and CKD and demonstrates the importance of lipid-lowering treatments in various metabolic diseases featured by lipid load, from the "rare" GSDIa to the "epidemic" morbid obesity or type 2 diabetes.

Clinical characteristics and muscle glycogen concentrations in warmblood horses with polysaccharide storage myopathy.

OBJECTIVE To characterize clinical findings for polysaccharide storage myopathy (PSSM) in warmblood horses with type 1 PSSM (PSSM1; caused by mutation of the glycogen synthase 1 gene) and type 2 PSSM (PSSM2; unknown etiology). SAMPLE Database with 3,615 clinical muscle biopsy submissions. PROCEDURES Reported clinical signs and serum creatine kinase (CK) and aspartate aminotransferase (AST) activities were retrospectively analyzed for horses with PSSM1 (16 warmblood and 430 nonwarmblood), horses with PSSM2 (188 warmblood and 646 nonwarmblood), and warmblood horses without PSSM (278). Lameness examinations were reviewed for 9 warmblood horses with PSSM2. Muscle glycogen concentrations were evaluated for horses with PSSM1 (14 warmblood and 6 nonwarmblood), warmblood horses with PSSM2 (13), and horses without PSSM (10 warmblood and 6 nonwarmblood). RESULTS Rhabdomyolysis was more common for horses with PSSM1 (12/16 [75%] warmblood and 223/303 [74%] nonwarmblood) and nonwarmblood horses with PSSM2 (221/436 [51%]) than for warmblood horses with PSSM2 (39/147 [27%]). Gait abnormality was more common in warmblood horses with PSSM2 (97/147 [66%]) than in warmblood horses with PSSM1 (1/16 [7%]), nonwarmblood horses with PSSM2 (176/436 [40%]), and warmblood horses without PSSM (106/200 [53%]). Activities of CK and AST were similar in warmblood horses with and without PSSM2. Muscle glycogen concentrations in warmblood and nonwarmblood horses with PSSM1 were significantly higher than concentrations in warmblood horses with PSSM2. CONCLUSIONS AND CLINICIAL RELEVANCE Rhabdomyolysis and elevated muscle glycogen concentration were detected in horses with PSSM1 regardless of breed. Most warmblood horses with PSSM2 had stiffness and gait abnormalities with CK and AST activities and muscle glycogen concentrations within reference limits.

[Characteristics of lipid metabolism and the cardiovascular system in glycogenosis types I and III]. / Kharakteristika lipidnogo obmena i sostoianie serdechno-sosudistoi sistemy pri glikogenozakh I i III tipov.

Glycogen storage disease (GSD) is an inherited metabolic disorder characterized by early childhood lipid metabolic disturbances with potentially proatherogenic effects. The review outlines the characteristics of impaired lipid composition and other changes in the cardiovascular system in GSD types I and III. It analyzes the factors enabling and inhibiting the development of atherosclerosis in patients with GSD. The review describes the paradox of vascular resistance to the development of early atherosclerosis despite the proatherogenic composition of lipids in the patients of this group.

Renal endoplasmic reticulum stress is coupled to impaired autophagy in a mouse model of GSD Ia.

GSD Ia (von Gierke Disease, Glycogen Storage Disease Type Ia) is a devastating genetic disorder with long-term sequelae, such as non-alcoholic fatty liver disease and renal failure. Down-regulated autophagy is involved in the development of hepatic metabolic dysfunction in GSD Ia; however, the role of autophagy in the renal pathology is unknown. Here we show that autophagy is impaired and endoplasmic reticulum (ER) stress is increased in the kidneys of a mouse model of GSD Ia. Induction of autophagy by rapamycin also reduces this ER stress. Taken together, these results show an additional role for autophagy down-regulation in the pathogenesis of GSD Ia, and provide further justification for the use of autophagy modulators in GSD Ia.

Cutting Edge: Increased Autoimmunity Risk in Glycogen Storage Disease Type 1b Is Associated with a Reduced Engagement of Glycolysis in T Cells and an Impaired Regulatory T Cell Function.

Glycogen storage disease type 1b (GSD-1b) is an autosomal-recessive disease caused by mutation of glucose-6-phosphate transporter and characterized by altered glycogen/glucose homeostasis. A higher frequency of autoimmune diseases has been observed in GSD-1b patients, but the molecular determinants leading to this phenomenon remain unknown. To address this question, we investigated the effect of glucose-6-phosphate transporter mutation on immune cell homeostasis and CD4+ T cell functions. In GSD-1b subjects, we found lymphopenia and a reduced capacity of T cells to engage glycolysis upon TCR stimulation. These phenomena associated with reduced expression of the FOXP3 transcription factor, lower suppressive function in peripheral CD4+CD25+FOXP3+ regulatory T cells, and an impaired capacity of CD4+CD25- conventional T cells to induce expression of FOXP3 after suboptimal TCR stimulation. These data unveil the metabolic determinant leading to an increased autoimmunity risk in GSD-1b patients.

Hepatic mitochondrial dysfunction is a feature of Glycogen Storage Disease Type Ia (GSDIa).

Glycogen storage disease type Ia (GSDIa, von Gierke disease) is the most common glycogen storage disorder. It is caused by the deficiency of glucose-6-phosphatase, an enzyme which catalyses the final step of gluconeogenesis and glycogenolysis. Clinically, GSDIa is characterized by fasting hypoglycaemia and hepatic glycogen and triglyceride overaccumulation. The latter leads to steatohepatitis, cirrhosis, and the formation of hepatic adenomas and carcinomas. Currently, little is known about the function of various organelles and their impact on metabolism in GSDIa. Accordingly, we investigated mitochondrial function in cell culture and mouse models of GSDIa. We found impairments in oxidative phosphorylation and changes in TCA cycle metabolites, as well as decreased mitochondrial membrane potential and deranged mitochondrial ultra-structure in these model systems. Mitochondrial content also was decreased, likely secondary to decreased mitochondrial biogenesis. These deleterious effects culminated in the activation of the mitochondrial apoptosis pathway. Taken together, our results demonstrate a role for mitochondrial dysfunction in the pathogenesis of GSDIa, and identify a new potential target for the treatment of this disease. They also provide new insight into the role of carbohydrate overload on mitochondrial function in other hepatic diseases, such as non-alcoholic fatty liver disease.

Evaluation of central nervous system in patients with glycogen storage disease type 1a.

We aimed to evaluate structure and functions of central nervous system (CNS) in children with glycogen storage disease (GSD) type 1a. Neurological examination, psychometric tests, electroencephalography (EEG), magnetic resonance imaging (MRI), visual evoked potentials (VEP) and brainstem auditory evoked potentials (BAEP) were performed. The results were compared between patients with good and poor metabolic control and healthy children. Twenty-three patients with GSD type 1a were studied. Twelve patients were in poor metabolic control group and 11 patients in good metabolic control group. Five patients had intellectual disability, 10 had EEG abnormalities, seven had abnormal VEP and two had abnormal BAEP results. MRI was abnormal in five patients. There was significant correlation between the number of hypoglycemic attacks and MRI abnormalities. Central nervous system may be affected in GSD type 1a even in patients with normal neurologic examination. Accumulation of abnormal results in patients with poor metabolic control supports the importance of metabolic control in GSD type 1a.

Progressive development of renal cysts in glycogen storage disease type I.

Glycogen storage disease type I (GSDI) is a rare metabolic disease due to glucose-6 phosphatase deficiency, characterized by fasting hypoglycemia. Patients also develop chronic kidney disease whose mechanisms are poorly understood. To decipher the process, we generated mice with a kidney-specific knockout of glucose-6 phosphatase (K.G6pc-/- mice) that exhibited the first signs of GSDI nephropathy after 6 months of G6pc deletion. We studied the natural course of renal deterioration in K.G6pc-/- mice for 18 months and observed the progressive deterioration of renal functions characterized by early tubular dysfunction and a later destruction of the glomerular filtration barrier. After 15 months, K.G6pc-/- mice developed tubular-glomerular fibrosis and podocyte injury, leading to the development of cysts and renal failure. On the basis of these findings, we were able to detect the development of cysts in 7 out of 32 GSDI patients, who developed advanced renal impairment. Of these 7 patients, 3 developed renal failure. In addition, no renal cysts were detected in six patients who showed early renal impairment. In conclusion, renal pathology in GSDI is characterized by progressive tubular dysfunction and the development of polycystic kidneys that probably leads to the development of irreversible renal failure in the late stages. Systematic observations of cyst development by kidney imaging should improve the evaluation of the disease's progression, independently of biochemical markers.

Muscle Ultrasound in Patients with Glycogen Storage Disease Types I and III.

In glycogen storage diseases (GSDs), improved longevity has resulted in the need for neuromuscular surveillance. In 12 children and 14 adults with the "hepatic" (GSD-I) and "myopathic" (GSD-III) phenotypes, we cross-sectionally assessed muscle ultrasound density (MUD) and muscle force. Children with both "hepatic" and "myopathic" GSD phenotypes had elevated MUD values (MUD Z-scores: GSD-I > 2.5 SD vs. GSD-III > 1 SD, p < 0.05) and muscle weakness (GSD-I muscle force; p < 0.05) of myopathic distribution. In "hepatic" GSD-I adults, MUD stabilized (GSD-I adults vs. GSD-I children, not significant), concurring with moderate muscle weakness (GSD-I adults vs. healthy matched pairs, p < 0.05). In "myopathic" GSD-III adults, MUD increased with age (MUD-GSD III vs. age: r = 0.71-0.83, GSD-III adults > GSD-III children, p < 0.05), concurring with pronounced muscle weakness (GSD-III adults vs. GSD-I adults, p < 0.05) of myopathic distribution. Children with "hepatic" and "myopathic" GSD phenotypes were both found to have myopathy. Myopathy stabilizes in "hepatic" GSD-I adults, whereas it progresses in "myopathic" GSD-III adults. Muscle ultrasonography provides an excellent, non-invasive tool for neuromuscular surveillance per GSD phenotype.

Hepatic glycogen storage disorders: what have we learned in recent years?

PURPOSE OF REVIEW: Glycogen storage disorders (GSDs) are inborn errors of metabolism with abnormal storage or utilization of glycogen. The present review focuses on recent advances in hepatic GSD types I, III and VI/IX, with emphasis on clinical aspects and treatment. RECENT FINDINGS: Evidence accumulates that poor metabolic control is a risk factor for the development of long-term complications, such as liver adenomas, low bone density/osteoporosis, and kidney disease in GSD I. However, mechanisms leading to these complications remain poorly understood and are being investigated. Molecular causes underlying neutropenia and neutrophil dysfunction in GSD I have been elucidated. Case series provide new insights into the natural course and outcome of GSD types VI and IX. For GSD III, a high protein/fat diet has been reported to improve (cardio)myopathy, but the beneficial effect of this dietary concept on muscle and liver disease manifestations needs to be further established in prospective studies. SUMMARY: Although further knowledge has been gained regarding pathophysiology, disease course, treatment, and complications of hepatic GSDs, more controlled prospective studies are needed to assess effects of different dietary and medical treatment options on long-term outcome and quality of life.

Glycogen storage disease type 1b: an early onset severe phenotype associated with a novel mutation (IVS4) in the glucose 6-phosphate translocase (SLC37A4) gene in a Turkish patient.

Glycogen storage disease type I (GSD-I) is a group of autosomal recessive disorders that include types Ia and Ib. GSD-Ib is caused by a deficiency in the glucose-6-phosphate transporter (G6PT) caused by a mutation in the SLC37A4 gene coding for G6PT. Glycogen storage disease is characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver and chronic neutropenia. Herein we describe a 4-month-old Turkish patient with early onset and severe typical clinical features of GSD-1b in which a novel mutation in the SLC37A4 gene was detected. After the bone marrow examination parenteral antibiotic therapy and subcutaneous granulocyte colony-stimulating factor (G-CSF) were started. Due to the severe neutropenia the patient had developed nosocomial sepsis and the dose of G-CSF was increased. After 2 months later from the initial treatment of the G-CSF he developed splenomegaly and urinary complications. Despite maximal therapy he had an extremely poor quality of life and life-threatening complications due to impaired bone marrow function. As the patient required continual hospitalization he was schedule for bone marrow transplantation.

[Mitochondrial dysfunction in children with hepatic forms of glycogen storage disease].

AIM: The purpose of the study was to assess mitochondrial dysfunction severity in patients with hepatic forms of glycogen storage disease (GSD). PATIENTS AND METHODS: We examined 53 children with GSD in the dynamics. Distribution of children by disease types was: 1st group--children with GSD type I, 2nd group--children with GSD type III, 3rd group--children with GSD type VI and IX; comparison group consisted of 34 healthy children. Intracellular dehydrogenases activity: succinate dehydrogenase (SDH), glycerol-3-phosphate-dehydrogenase (GPDH). nicotinamideadenin-H-dehydrogenase (NADH-D) and lactatdehydrogenase (LDH) was measured using the quantitative cytochemical method in the peripheral lymphocytes. RESULTS: It was revealed decrease of SDH- (p < 0.001) and GPDH-activities (p < 0.001), along with increase of the NADH-D activity (p < 0.05) in all patients with GSD, (SDH/ NADH-D) index was decreased (p < 0.001). LDH activity was increased in groups 1 (p < 0.05) and 3 (p < 0.01), compared with comparison group. The most pronounced intracellular enzymes activity deviations were observed in children with GSD type I, that correspond to more severe clinical form of GSD. It was found strong correlation between intracellular enzymes activity and both hepatomegaly level (R = 0.867) and metabolic acidosis severity (R = 0.987). CONCLUSION: Our investigation revealed features of mitochondrial dysfunction in children with GSD, depending on the GSD type. Activities of lymphocytes enzymes correlates with the main disease severity parameters and can be used as an additional diagnostic criteria in children with hepatic form of GSD.

[History case of multiple hepatic adenomas in adolescent with severe course of glycogen storage disease type lb].

We represented a case history of multiple hepatic adenomas in an adolescent with severe clinical course of glycogen storage disease type lb (compound heterozygous mutations c.1042_1043delCT and c.817G>A in the SLC37A4). The patient was prescribed a raw cornstarch and hepatoprotectors therapy, but he and his parents had low compliance to treatment. At the age of 13,5 years ultrasound investigation and computed tomography revealed multiple adenomas. Due to the severe condition of the patient it was impossible to perform focal hepatic biopsy. At present time the patient receives treatment focused on correction of metabolic disturbances, thereafter an applicability of exploratory puncture will be settled for the further patient surveillance. The modern data on causes and risk factors of hepatic adenomas in such patients, the possibility of their malignization, the algorithm of the follow-up and the methods of treatment are presented in the discussion.

Could GSD type I expand the spectrum of disorders with elevated plasma chitotriosidase activity?

Glycogen storage disease type I (GSDI) is characterized by accumulation of glycogen and fat in the liver and kidneys, resulting in hepatomegaly and renomegaly. Human chitotriosidase is a recently described fully active chitinase expressed by activated macrophages. Marked elevation of chitotriosidase activity was initially observed in plasma of patients with Gaucher disease. Subsequently, elevation was also observed in various lysosomal storage disorders such as fucosidosis, galactosialidosis and glycogen storage disease type IV. The aim of the present study was to evaluate plasma chitotriosidase activity in 19 children with glycogen storage disease type I. Plasma chitotriosidase levels were found to be significantly higher in children with GSD type I than healthy age-matched controls (21.3 ± 16.4 vs. 12.3 ± 8.9 nmol/h/mL, p=0.04). All the patients reported here presented with hepatomegaly. Our report expands the spectrum of disorders that should be included in the differential diagnosis of patients with increased plasma chitotriosidase activity, irrespective of the mechanisms involved.

A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations.

The G6PC3 gene encodes the ubiquitously expressed glucose-6-phosphatase enzyme (G-6-Pase ß or G-6-Pase 3 or G6PC3). Bi-allelic G6PC3 mutations cause a multi-system autosomal recessive disorder of G6PC3 deficiency (also called severe congenital neutropenia type 4, MIM 612541). To date, at least 57 patients with G6PC3 deficiency have been described in the literature.G6PC3 deficiency is characterized by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia in many patients, a prominent superficial venous pattern and a high incidence of congenital cardiac defects and uro-genital anomalies. The phenotypic spectrum of the condition is wide and includes rare manifestations such as maturation arrest of the myeloid lineage, a normocellular bone marrow, myelokathexis, lymphopaenia, thymic hypoplasia, inflammatory bowel disease, primary pulmonary hypertension, endocrine abnormalities, growth retardation, minor facial dysmorphism, skeletal and integument anomalies amongst others. Dursun syndrome is part of this extended spectrum. G6PC3 deficiency can also result in isolated non-syndromic severe neutropenia. G6PC3 mutations in result in reduced enzyme activity, endoplasmic reticulum stress response, increased rates of apoptosis of affected cells and dysfunction of neutrophil activity.In this review we demonstrate that loss of function in missense G6PC3 mutations likely results from decreased enzyme stability. The condition can be diagnosed by sequencing the G6PC3 gene. A number of G6PC3 founder mutations are known in various populations and a possible genotype-phenotype relationship also exists. G6PC3 deficiency should be considered as part of the differential diagnoses in any patient with unexplained congenital neutropenia.Treatment with G-CSF leads to improvement in neutrophil numbers, prevents infections and improves quality of life. Mildly affected patients can be managed with prophylactic antibiotics. Untreated G6PC3 deficiency can be fatal. Echocardiogram, renal and pelvic ultrasound scans should be performed in all cases of suspected or confirmed G6PC3 deficiency. Routine assessment should include biochemical profile, growth profile and monitoring for development of varicose veins or venous ulcers.

Glycogen storage disease type 1 and diabetes: learning by comparing and contrasting the two disorders.

Glycogen storage disease type 1 (GSD1) and diabetes may look at first like totally opposite disorders, as diabetes is characterized by uncontrolled hyperglycaemia, whereas GSD1 is characterized by severe fasting hypoglycaemia. Diabetes is due to a failure to suppress endogenous glucose production (EGP) in the postprandial state because of either a lack of insulin or insulin resistance. In contrast, GSD1 is characterized by a lack of EGP. However, both diseases share remarkably similar patterns in terms of pathophysiology such as the long-term progression of renal dysfunction and hepatic steatosis leading to renal failure and the development of hepatic tumours, respectively. Thus, much may be learned from considering the similarities between GSD1 and diabetes, especially in the metabolic pathways underlying nephropathy and fatty liver, and perhaps even more from their differences. In this review, the differences between diabetes and GSD1 are first highlighted, as both are characterized by alterations in EGP. The molecular pathways involved in liver pathologies, including steatosis, hepatomegaly (glycogenic hepatopathy) and the development of liver tumours are also compared. These pathologies are mainly due to the accumulation of lipids and/or glycogen in hepatocytes. Finally, the similar pathways leading to nephropathy in both diabetic and GSD1 patients are described. In conclusion, comparisons of these pathologies should lead to a better understanding of the crucial role of EGP in the control of glucose and energy homoeostasis. Moreover, it may highlight similar therapeutic targets for the two disorders. Thus, this review suggests that the treatment of adult patients with either GSD1 or diabetes could be carried out by the same specialists-diabetologists.

Pathogenesis of growth failure and partial reversal with gene therapy in murine and canine Glycogen Storage Disease type Ia.

Glycogen Storage Disease type Ia (GSD-Ia) in humans frequently causes delayed bone maturation, decrease in final adult height, and decreased growth velocity. This study evaluates the pathogenesis of growth failure and the effect of gene therapy on growth in GSD-Ia affected dogs and mice. Here we found that homozygous G6pase (-/-) mice with GSD-Ia have normal growth hormone (GH) levels in response to hypoglycemia, decreased insulin-like growth factor (IGF) 1 levels, and attenuated weight gain following administration of GH. Expression of hepatic GH receptor and IGF 1 mRNAs and hepatic STAT5 (phospho Y694) protein levels are reduced prior to and after GH administration, indicating GH resistance. However, restoration of G6Pase expression in the liver by treatment with adeno-associated virus 8 pseudotyped vector expressing G6Pase (AAV2/8-G6Pase) corrected body weight, but failed to normalize plasma IGF 1 in G6pase (-/-) mice. Untreated G6pase (-/-) mice also demonstrated severe delay of growth plate ossification at 12 days of age; those treated with AAV2/8-G6Pase at 14 days of age demonstrated skeletal dysplasia and limb shortening when analyzed radiographically at 6 months of age, in spite of apparent metabolic correction. Moreover, gene therapy with AAV2/9-G6Pase only partially corrected growth in GSD-Ia affected dogs as detected by weight and bone measurements and serum IGF 1 concentrations were persistently low in treated dogs. We also found that heterozygous GSD-Ia carrier dogs had decreased serum IGF 1, adult body weights and bone dimensions compared to wild-type littermates. In sum, these findings suggest that growth failure in GSD-Ia results, at least in part, from hepatic GH resistance. In addition, gene therapy improved growth in addition to promoting long-term survival in dogs and mice with GSD-Ia.

Multiple roles of glucose-6-phosphatases in pathophysiology: state of the art and future trends.

BACKGROUND: The endoplasmic reticulum enzyme glucose-6-phosphatase catalyzes the hydrolysis of glucose-6-phosphate to glucose and inorganic phosphate. The enzyme is a part of a multicomponent system that includes several integral membrane proteins; the catalytic subunit (G6PC) and transporters for glucose-6-phosphate, inorganic phosphate and glucose. The G6PC gene family presently includes three members, termed as G6PC, G6PC2, and G6PC3. Although the three isoforms show a moderate amino acid sequence homology, their membrane topology and catalytic site are very similar. The isoforms are expressed differently in various tissues. Mutations in all three genes have been reported to be associated with human diseases. SCOPE OF REVIEW: The present review outlines the biochemical features of the G6PC gene family products, the regulation of their expression, their role in the human pathology and the possibilities for pharmacological interventions. MAJOR CONCLUSIONS: G6PCs emerge as integrators of extra- and intracellular glucose homeostasis. Beside the well known key role in blood glucose homeostasis, the members of the G6PC family seem to play a role as sensors of intracellular glucose and of intraluminal glucose/glucose-6-phosphate in the endoplasmic reticulum. GENERAL SIGNIFICANCE: Since mutations in the three G6PC genes can be linked to human pathophysiological conditions, the better understanding of their functioning in connection with genetic alterations, altered expression and tissue distribution has an eminent importance.

Fertility and pregnancy in women affected by glycogen storage disease type I, results of a multicenter Italian study.

BACKGROUND: Life expectancy of patients with glycogen storage disease (GSD) type I has improved considerably, opening new problems correlated with adult age. In females polycystic ovaries (PCOs) has been described as frequently associated with the disease, however successful pregnancies have been reported. Whether or not GSD I is associated with impaired reproductive function is still unclear. PATIENTS AND METHODS: Data about female patients with GSD Ia and Ib, who were 16 years or older, were obtained from clinical records and interviews. RESULTS: A total of 32 women with GSD I (25 GSD Ia, 7 GSD Ib), median age 26 years (range 16-55), were included. 9/32 patients had delayed menarche, 17/32 had irregular cycles, 8/22 had documented polycystic ovaries. Five successful spontaneous pregnancies in four patients with GSD Ia and two in a woman with GSD Ib were reported. The latter had development and enlargement of hepatic adenomas during pregnancies. CONCLUSION: Despite the high prevalence of irregular menstruation cycles and polycystic ovaries, fertility seems not to be impaired in women with GSD I. During pregnancy monitoring for adenoma development is mandatory.