Glucose-6-phosphatase deficiency

Glucose-6-phosphatase deficiency (G6P deficiency), or glycogen storage disease type I (GSDI), is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, between the ages of 3 to 4 months by symptoms of hypoglycemia (tremors, seizures, cyanosis, apnea). Patients have poor tolerance to fasting, marked hepatomegaly, growth retardation (small stature and delayed puberty), generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, full-cheeked round face, enlarged kydneys and platelet dysfunctions leading to frequent epistaxis. In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphtous gingivostomatitis, and inflammatory bowel disease. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma) and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency). GSDI is caused by a dysfunction in the G6P system, a key step in the regulation of glycemia. The deficit concerns the catalytic subunit G6P-alpha (type Ia) which is restricted to expression in the liver, kidney and intestine, or the ubiquitously expressed G6P transporter (type Ib). Mutations in the genes G6PC (17q21) and SLC37A4 (11q23) respectively cause GSDIa and Ib. Many mutations have been identified in both genes,. Transmission is autosomal recessive. Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon. It can be confirmed by demonstrating a deficient activity of a G6P system component in a liver biopsy. To date, the diagnosis is most commonly confirmed by G6PC (GSDIa) or SLC37A4 (GSDIb) gene analysis, and the indications of liver biopsy to measure G6P activity are getting rarer and rarer. Differential diagnoses include the other GSDs, in particular type III (see this term). However, in GSDIII, glycemia and lactacidemia are high after a meal and low after a fast period (often with a later occurrence than that of type I). Primary liver tumors and Pepper syndrome (hepatic metastases of neuroblastoma) may be evoked but are easily ruled out through clinical and ultrasound data. Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villous cells. Pre-implantatory genetic diagnosis may also be discussed. Genetic counseling should be offered to patients and their families. The dietary treatment aims at avoiding hypoglycemia (frequent meals, nocturnal enteral feeding through a nasogastric tube, and later oral addition of uncooked starch) and acidosis (restricted fructose and galactose intake). Liver transplantation, performed on the basis of poor metabolic control and/or hepatocarcinoma, corrects hypoglycemia, but renal involvement may continue to progress and neutropenia is not always corrected in type Ib. Kidney transplantation can be performed in case of severe renal insufficiency. Combined liver-kidney grafts have been performed in a few cases. Prognosis is usually good: late hepatic and renal complications may occur, however, with adapted management, patients have almost normal life span

Glucose-6-phosphatase deficiency

Glucose-6-phosphatase deficiency (G6P deficiency), or glycogen storage disease type I (GSDI), is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, between the ages of 3 to 4 months by symptoms of hypoglycemia (tremors, seizures, cyanosis, apnea). Patients have poor tolerance to fasting, marked hepatomegaly, growth retardation (small stature and delayed puberty), generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, full-cheeked round face, enlarged kydneys and platelet dysfunctions leading to frequent epistaxis. In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphtous gingivostomatitis, and inflammatory bowel disease. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma) and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency). GSDI is caused by a dysfunction in the G6P system, a key step in the regulation of glycemia. The deficit concerns the catalytic subunit G6P-alpha (type Ia) which is restricted to expression in the liver, kidney and intestine, or the ubiquitously expressed G6P transporter (type Ib). Mutations in the genes G6PC (17q21) and SLC37A4 (11q23) respectively cause GSDIa and Ib. Many mutations have been identified in both genes,. Transmission is autosomal recessive. Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon. It can be confirmed by demonstrating a deficient activity of a G6P system component in a liver biopsy. To date, the diagnosis is most commonly confirmed by G6PC (GSDIa) or SLC37A4 (GSDIb) gene analysis, and the indications of liver biopsy to measure G6P activity are getting rarer and rarer. Differential diagnoses include the other GSDs, in particular type III (see this term). However, in GSDIII, glycemia and lactacidemia are high after a meal and low after a fast period (often with a later occurrence than that of type I). Primary liver tumors and Pepper syndrome (hepatic metastases of neuroblastoma) may be evoked but are easily ruled out through clinical and ultrasound data. Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villous cells. Pre-implantatory genetic diagnosis may also be discussed. Genetic counseling should be offered to patients and their families. The dietary treatment aims at avoiding hypoglycemia (frequent meals, nocturnal enteral feeding through a nasogastric tube, and later oral addition of uncooked starch) and acidosis (restricted fructose and galactose intake). Liver transplantation, performed on the basis of poor metabolic control and/or hepatocarcinoma, corrects hypoglycemia, but renal involvement may continue to progress and neutropenia is not always corrected in type Ib. Kidney transplantation can be performed in case of severe renal insufficiency. Combined liver-kidney grafts have been performed in a few cases. Prognosis is usually good: late hepatic and renal complications may occur, however, with adapted management, patients have almost normal life span

Stress osmotique et production de cytokines proinflammatoires dans une lignée cellulaire intestinale Caco-2/TC7

L'intestin est un organe clé dans les réponses immunitaire et inflammatoire. La réponse inflammatoire intestinale, qu'elle soit locale ou dans le cadre d'une réponse systémique, peut par la production importante et non contrôlée des médiateurs de l'inflammation avoir un effet délétère, entraînant des lésions intestinales. Dans ce travail, nous avons étudié l'effet d'un stress osmotique, qu'il soit hypo- ou hyper-osmolaire, sur la production de deux cytokines proinflammatoires, l'IL-6 et l'IL-8, par les cellules de la lignée cellulaire intestinale Caco-2/TC7. Nous avons ensuite comparé l'effet inducteur du stress osmotique à celui de stimuli proinflammatoires connus et également étudié les effets potentiels de synergie ou d'additivité de tels stimuli inflammatoires. Enfin, nous avons essayé de préciser la voie de signalisation impliquée dans l'effet du stress osmotique en se focalisant sur l'IL-8. Pour cela, nous avons étudié l'implication potentielle de différentes MAPK ainsi que celle de protéine tyrosine kinases. L'ensemble des résultats montre que les cellules Caco-2/TC7 produisent de façon constitutive la chimiokine IL-8 et que la production de celle-ci est minimale en condition isoosmolaire. A l'opposé, aucune production d'IL-6 n'est détectable dans ces conditions expérimentales. Le stress osmotique, qu'il soit hypo- ou hyper-osmolaire, entraîne une augmentation de la production d'IL-8 et induit celle d'IL-6. Les résultats montrent également que la variation de l'osmolarité du milieu induit un effet stimulateur sur les productions d'IL-6 et d'IL-8, effet qui est, au moins en partie, additif à celui de l'IL-1b. Concernant le stress hypoosmolaire, l'ensemble des résultats montrent qu'une protéine kinase de la famille JNK et que la déphosphorylation d'une protéine sur un résidu tyrosyle sont impliquées dans la voie de signalisation de ce type de stress. De plus, le stress hypoosmolaire agit, au moins en partie, par activation du facteur NF-kB. Concernant le stress hyperosmolaire, aucune des trois protéines MAP Kinases étudiées (p38MAPK, JNK et p42/44MAPK) n'est impliquée dans ce type de stress. De même, la phosphorylation d'une protéine sur un résidu tyrosyle n'est pas spécifiquement impliquée dans l'effet du stress hyperosmolaire. La voie de signalisation mise en jeu lors d'un stress hyperosmolaire reste donc à identifier. En conclusion, ces résultats démontrent que le stress osmotique per se est un signal de type proinflammatoire dans les cellules Caco-2/TC7 et suggèrent qu'un osmosensor pourrait exister dans les cellules épithéliales intestinalesThe intestine play a key role in the immune and inflammatory response. Local or systemic intestinal inflammatory response could be deleterious by the uncontrolled and massive production of inflammatory mediators leading to intestinal damages. In the present study, the effect of hyper- and hypoosmotic stresses on the production of two proinflammatory cytokines, IL-6 and IL-8 were investigated in the intestinal epithelial cell line Caco-2/TC7. We also studied the potential additivity of to that induced by proinflammatory cytokines and tried to specify the signalling pathway involved in the effect of osmotic stress focusing on IL-8 production. For this purpose, different MAPK and protein tyrosine kinases pathways have been investigated. The results obtained show that Caco-2 cells constitutively produce the chemokine IL-8. IL-8 production is minimal under isoosmolar condition whereas IL-6 production is undetectable under these experimental conditions. Hyper- and hypoosmotic stresses both (i) enhance the endogenous production of IL-8 and induce that of IL-6, and (ii) reinforce cytokine production induced by IL-1ß. Regarding the hypoosmotic stress, the results show the involvement of (i) the protein c-jun-NH2-terminal kinase (JNK) and (ii) the protein tyrosine kinase. This is not the case for hyperosmolarity. The signalling for hyperosmotic stress remains still unknown. Moreover, hypoosmotic stress acts partially through activation of the transcription factor. Taken together, these results demonstrate that osmotic stress is a proinflammatory signal in Caco-2 cells and suggest that an osmosensor might specifically exist in intestinal epithelial cells.ROUEN-BU Sciences (764512102) / SudocSudocFranceF

Progressive development of renal cysts in glycogen storage disease type I

International audienceGlycogen 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

Comparison of machine perfusion versus cold storage in kidney transplant recipients from expanded criteria donors: a cohort-based study

International audienceBackground Most studies comparing the efficacy of hypothermic machine perfusion (HMP) versus static cold storage (SCS) are based on short-term outcomes. We aimed to better evaluate the mid-term impact of HMP in patients receiving expanded criteria donor (ECD) kidneys. Methods The analyses were based on the French Données Informatisées et VAlidées en Transplantation (DIVAT) observational cohort. Patients aged ≥45 years transplanted for the first or second times from an ECD donor since 2010 were studied. Our study reported the graft and/or patient survivals and the incidence of acute rejection episode. The Cox models and the Kaplan–Meier estimators, weighted on the propensity score, were used to study the times-to-events. Results Among the 2019 included patients, 1073 were in the SCS group versus 946 in the HMP group. The mean life expectancy with functioning graft was 5.7 years [95% confidence interval (CI) 5.4–6.1] for the HMP cohort followed-up for 8 years post-transplantation versus 6.0 years (95% CI 5.7–6.2) for the SCS group. These mid-term results were comparable in the patients receiving grafts from donors aged ≥70 years and in the transplantations with cold ischaemia time ≥18 h. Conclusions Our study challenges the utility of using HMP to improve mid-term patient and graft survival. Nevertheless, the improvement of the short-term outcomes is indisputable. It is necessary to continue technological innovations to obtain long-term results