Euglycemic Diabetic Ketoacidosis Presenting as Hypoglycemia in a Patient With Type 2 Diabetes and Von Gierke's Disease.

Von Gierke's disease (VGD) is rarely associated with type 2 diabetes mellitus (DM2). We present a case of VGD with DM2 that presented with hypoglycemia in the setting of diabetic ketoacidosis (DKA) in a young male with VGD using the sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin. The patient required resuscitation with fluids containing glucose prior to the administration of insulin for DKA protocol with significant clinical improvement. This case demonstrates a rare presentation of DKA with hypoglycemia.

Inhibition of Wnt/ß-catenin signaling reduces renal fibrosis in murine glycogen storage disease type Ia.

Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in the enzyme glucose-6-phosphatase-α (G6Pase-α or G6PC) that is expressed primarily in the gluconeogenic organs, namely liver, kidney cortex, and intestine. Renal G6Pase-α deficiency in GSD-Ia is characterized by impaired gluconeogenesis, nephromegaly due to elevated glycogen accumulation, and nephropathy caused, in part, by renal fibrosis, mediated by activation of the renin-angiotensin system (RAS). The Wnt/ß-catenin signaling regulates the expression of a variety of downstream mediators implicated in renal fibrosis, including multiple genes in the RAS. Sustained activation of Wnt/ß-catenin signaling is associated with the development and progression of renal fibrotic lesions that can lead to chronic kidney disease. In this study, we examined the molecular mechanism underlying GSD-Ia nephropathy. Damage to the kidney proximal tubules is known to trigger acute kidney injury (AKI) that can, in turn, activate Wnt/ß-catenin signaling. We show that GSD-Ia mice have AKI that leads to activation of the Wnt/ß-catenin/RAS axis. Renal fibrosis was demonstrated by increased renal levels of Snail1, α-smooth muscle actin (α-SMA), and extracellular matrix proteins, including collagen-Iα1 and collagen-IV. Treating GSD-Ia mice with a CBP/ß-catenin inhibitor, ICG-001, significantly decreased nuclear translocated active ß-catenin and reduced renal levels of renin, Snail1, α-SMA, and collagen-IV. The results suggest that inhibition of Wnt/ß-catenin signaling may be a promising therapeutic strategy for GSD-Ia nephropathy.

Development of hepatocellular adenomas in a patient with glycogen storage disease Ia treated with growth hormone therapy.

Glycogen storage disease Ia (GSD Ia), also known as von Gierke disease, is caused by pathogenic variants in the G6PC1 gene (OMIM 232200) which encodes glucose-6-phosphatase. Deficiency of glucose-6-phosphatase impairs the processes of gluconeogenesis and glycogenolysis by preventing conversion of glucose-6-phosphate to glucose. Clinical features include fasting hypoglycemia, lactic acidosis, hypertriglyceridemia, hyperuricemia, hepatomegaly, and development of hepatocellular adenomas (HCAs) with potential for malignant transformation. Additionally, patients with GSD Ia often exhibit short stature, in some instances due to growth hormone (GH) deficiency. Patients with short stature caused by GH deficiency typically receive GH injections. Here, we review the literature and describe a female with GSD Ia who had short stature, failure of growth progression, and suspected GH deficiency. This patient received GH injections from ages 11 to 14 years under careful monitoring of an endocrinologist and developed HCAs during that time. To date, there is no reported long-term follow up data on patients with GSD Ia who have received GH therapy, and therefore the clinical outcomes post-GH therapy are unclear.

Von Gierke Disease (Glycogen Storage Disease Type I) and Life-Threatening Abdominal Aortic Aneurysm: A Case Report of an Extremely Rare Condition.

Von Gierke disease, also known as glycogen storage disease type I, co-existent with an abdominal aortic aneurysm (AAA), is an extremely rare combination of diseases that requires challenging therapeutic measures. We present, for the first time in literature, the case of a 62-year-old female with von Gierke disease who required open surgical repair of an AAA with challenging neck anatomy outside of instructions for use of endovascular repair. Even though the surgical risks for life-threatening complications, such as pancreatitis, metabolic acidosis, and kidney failure, were high, the 6-month postoperative course was uneventful. Despite the invasiveness of the treatment, surgery to treat the AAA was safe and effective. Further data is needed to draw robust conclusions about the treatment of choice for those patients with diseases in co-existence with AAAs.

Genome editing using Staphylococcus aureus Cas9 in a canine model of glycogen storage disease Ia.

Glycogen storage disease type Ia (GSD Ia) is the inherited deficiency of glucose-6-phosphatase (G6Pase), associated with life-threatening hypoglycemia and long-term complications, including hepatocellular carcinoma formation. Gene replacement therapy fails to stably reverse G6Pase deficiency. We attempted genome editing using two adeno-associated virus vectors, one that expressed Staphylococcus aureus Cas9 protein and a second containing a donor transgene encoding G6Pase, in a dog model for GSD Ia. We demonstrated donor transgene integration in the liver of three adult-treated dogs accompanied by stable G6Pase expression and correction of hypoglycemia during fasting. Two puppies with GSD Ia were treated by genome editing that achieved donor transgene integration in the liver. Integration frequency ranged from 0.5% to 1% for all dogs. In adult-treated dogs, anti-SaCas9 antibodies were detected before genome editing, reflecting prior exposure to S. aureus. Nuclease activity was low, as reflected by a low percentage of indel formation at the predicted site of SaCas9 cutting that indicated double-stranded breaks followed by non-homologous end-joining. Thus, genome editing can integrate a therapeutic transgene in the liver of a large animal model, either early or later in life, and further development is warranted to provide a more stable treatment for GSD Ia.

Links between autophagy and disorders of glycogen metabolism - Perspectives on pathogenesis and possible treatments.

The glycogen storage diseases are a group of inherited metabolic disorders that are characterized by specific enzymatic defects involving the synthesis or degradation of glycogen. Each disorder presents with a set of symptoms that are due to the underlying enzyme deficiency and the particular tissues that are affected. Autophagy is a process by which cells degrade and recycle unneeded or damaged intracellular components such as lipids, glycogen, and damaged mitochondria. Recent studies showed that several of the glycogen storage disorders have abnormal autophagy which can disturb normal cellular metabolism and/or mitochondrial function. Here, we provide a clinical overview of the glycogen storage disorders, a brief description of autophagy, and the known links between specific glycogen storage disorders and autophagy.

Edgar von Gierke (1877-1945) - Eponym of "von Gierke disease" and double victim of National Socialism.

As recent studies on the Third Reich have shown, a two-digit number of Jewish pathologists fell victim to National Socialist repression. One of them was Edgar von Gierke. His name is nowadays best known in medicine for discovering the "von Gierke disease" - also classified as "Glycogen storage disease type I" - which he first described in 1929. This article deals with the role of von Gierke as a persecuted and disenfranchised Jew. Accordingly, the focus is on von Gierke's repressive experiences in the Third Reich, which were quite different from other cases. It is based on (1) previously partly unnoticed archival sources and (2) a re-analysis of the relevant research literature. The paper shows that Edgar von Gierke was a double victim of Nazi Germany, even though he was able to maintain his professional position for a comparatively long time: In contrast to other Jews who were dismissed in 1933 on the basis of the "Aryan paragraph", von Gierke benefited from a legal exception as a decorated front fighter in the First World War. It was not until 1937 that he was released from public service. Even more striking is the fact that von Gierke was ordered back to his old position twice between 1939 and 1944 due to a lack of personnel. The evaluation of archival files leads to the conclusion that von Gierke was recalled to work under pressure from leading National Socialists and that this ordered reappointment had a devastating effect on his health status. At that time the pathologist was already suffering from a progressive heart disease, to which he succumbed in autumn 1945 - fatally only a few month after the fall of the Third Reich.

Pathogenesis of Hepatic Tumors following Gene Therapy in Murine and Canine Models of Glycogen Storage Disease.

Glycogen storage disease type Ia (GSD Ia) is caused by mutations in the glucose-6-phosphatase (G6Pase) catalytic subunit gene (G6PC). GSD Ia complications include hepatocellular adenomas (HCA) with a risk for hepatocellular carcinoma (HCC) formation. Genome editing with adeno-associated virus (AAV) vectors containing a zinc-finger nuclease (ZFN) and a G6PC donor transgene was evaluated in adult mice with GSD Ia. Although mouse livers expressed G6Pase, HCA and HCC occurred following AAV vector administration. Interestingly, vector genomes were almost undetectable in the tumors but remained relatively high in adjacent liver (p < 0.01). G6Pase activity was decreased in tumors, in comparison with adjacent liver (p < 0.01). Furthermore, AAV-G6Pase vector-treated dogs with GSD Ia developed HCC with lower G6Pase activity (p < 0.01) in comparison with adjacent liver. AAV integration and tumor marker analysis in mice revealed that tumors arose from the underlying disorder, not from vector administration. Similarly to human GSD Ia-related HCA and HCC, mouse and dog tumors did not express elevated α-fetoprotein. Taken together, these results suggest that AAV-mediated gene therapy not only corrects hepatic G6Pase deficiency, but also has potential to suppress HCA and HCC in the GSD Ia liver.

A Novel Mutation in a Newborn Baby Leading to Glycogen Storage Disease Type Ia.

Glycogen storage disease type Ia (GSD1A) is caused by mutations in the G6PC gene. The G6PC gene was first cloned in 1993. Since then, many different mutations have been identified leading to this disease. Hepatomegaly is one of the important clinical manifestations of the disease. A 23-day-old girl was admitted to the hospital due to respiratory distress. Her physical examination was normal except for tachypnea. She had hypoglycemia, lactic academia, hyperlipidemia and hyperuricemia. With these clinical findings, GSD1A was considered in the patient and the diagnosis was genetically confirmed. By direct sequencing of the G6PC gene, we identified a novel homozygous variation (c.137T>G/p.Leu46Arg) in the patient and the healthy mother and father were heterozygotes for the variant. Here we present a case with a novel homozygous missense mutation c.137T>G/p.Leu46Arg in the G6PC gene leading to GSD1A clinical findings except early hepatomegaly. These findings expand the spectrum of causative mutations, and clinical findings in GSD1A.

Dietary Therapy for Von Gierke's Disease: A Case Report.

Von Gierke's disease, also known as glycogen storage disease (GSD) type 1A, is an autosomal recessive disease in which there is an inability to cleave glycogen to glucose because of a glucose 6 phosphate deficiency resulting in hypoglycemia and lactic acidosis. The patient may present with hepatomegaly and signs and symptoms of hypoglycemia. We diagnosed a case of Von Gierke's disease in a seven-month-old female infant who was admitted for abdominal distension, vomiting, and lethargy for a duration of four months with characteristic rounded doll's face, fatty cheeks, protuberant abdomen, and massive hepatomegaly. Lab investigations showed low hemoglobin, low blood sugar level, lactic acidosis, hyperlipidemia, hyperuricemia, mild elevation of liver enzymes, and high anion gap metabolic acidosis. The diagnosis was confirmed with a liver biopsy and dietary treatment was started. This case report highlights the value of dietary therapy in improving the quality of life and survival and minimizing complications.

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.

Induction of autophagy improves hepatic lipid metabolism in glucose-6-phosphatase deficiency.

BACKGROUND & AIMS: Glucose-6-phosphatase (G6Pase α, G6PC) deficiency, also known as von Gierke's disease or GSDIa, is the most common glycogen storage disorder. It is characterized by a decreased ability of the liver to convert glucose-6-phosphate (G6P) to glucose leading to glycogen and lipid over-accumulation progressing to liver failure and/or hepatomas and carcinomas. Autophagy of intracellular lipid stores (lipophagy) has been shown to stimulate fatty acid ß-oxidation in hepatic cells. Thus, we examined autophagy and its effects on reducing hepatic lipid over-accumulation in several cell culture and animal models of GSDIa. METHODS: Autophagy in G6PC-deficient hepatic cell lines, mice, and dogs was measured by Western blotting for key autophagy markers. Pro-autophagic Unc51-like kinase 1 (ULK1/ATG1) was overexpressed in G6PC-deficient hepatic cells, and lipid clearance and oxidative phosphorylation measured. G6PC(-/-) mice and GSDIa dogs were treated with rapamycin and assessed for liver function. RESULTS: Autophagy was impaired in the cell culture, mouse, and canine models of GSDIa. Stimulation of the anti-autophagic mTOR, and inhibition of the pro-autophagic AMPK pathways occurred both in vitro and in vivo. Induction of autophagy by ULK1/ATG1 overexpression decreased lipid accumulation and increased oxidative phosphorylation in G6PC-deficient hepatic cells. Rapamycin treatment induced autophagy and decreased hepatic triglyceride and glycogen content in G6PC(-/-) mice, as well as reduced liver size and improved circulating markers of liver damage in GSDIa dogs. CONCLUSIONS: Autophagy is impaired in GSDIa. Pharmacological induction of autophagy corrects hepatic lipid over-accumulation and may represent a new therapeutic strategy for GSDIa.

Glucogénesis: caracterización clínica - patológica del primer caso descrito en Bolivia en un paciente pediátrico / Glycogen storage disease: first clinicopathologic pediatric case described in Bolivia

Las glucogenosis son enfermedades hereditarias del metabolismo del glucógeno. Se reconocen más de 12 tipos y afectan principalmente al hígado y al músculo, mismas que se clasifican según la enzima defectuosa y el órgano afectado. Presentamos el caso de un niño de 4 años y 6 meses con hepatomegalia importante, retardo del crecimiento pondoestatural, extremidades delgadas, facies con mejillas redondas. Sus exámenes laboratoriales revelaron: hipoglicemia, hiperlipidemia, hiperuricemia y sus estudios imagenológicos evidenciaron hepatomegalia difusa severa. El estudio histopatológico concluyó con glucogenosis, no pudiendo definirse el tipo, por la imposibilidad de realizar pruebas específicas de histoquímica en Bolivia. El paciente es seguido por consulta externa, bajo indicaciones dietéticas para prevenir complicaciones.

Glycogen storage diseases are inherited metabolic disorders of glycogen metabolism. There are over 12 types, they may affect primarily the liver and muscle. They are classified and the affected tissue. The case of a 4 y 6m old-male infant is presented, with growth retardation, thin limbs, rounded cheeks. Laboratory testing showed hypoglycemia, hyperlipidermia, hyperuricemia. Imagenoly testing showed severe diffuse hepatomegaly. Histopathology concluded in glycogen storage disease, the enzyme deficiency could not be established because of the unavailability of these test in Bolivia. The patient is followed by consult, diet therapy to prevent complications.

The extraordinary career of Professor Dr. Simon van Creveld.

Simon van Creveld received both the MD and PhD degrees and had a multifaceted medical and scientific education at many hospitals and research institutes in the Netherlands, Germany, and the UK. He and his wife were the first to develop insulin for the Netherlands. His major interests were in hemophilia and hemorrhagic disorders, which accounted for 87 of his publications. In 1934, van Creveld demonstrated that a dispersed protein fraction obtained from serum could reduce the clotting time of hemophilic blood. His interest in glycogen storage disease resulted in van Creveld-von Gierke disease for which van Creveld contributed four published articles. The Ellis-van Creveld syndrome, also known as chondroectodermal dysplasia, was published in 1940 and became well known to medical geneticists. During the Nazi occupation of the Netherlands, van Creveld's professorship was taken away from him because he was Jewish. His visits to hospitals of concentration camps to treat babies and give pediatric advice while wearing a Jewish Yellow Star and interacting with SS Commandants in charge, and then leaving can only be described as amazing. After the war, his professorship was returned, and in the same year as his retirement, he established a large Hemophila Treatment and Research Center now known as the Van Creveld Clinic, which celebrated its 40th anniversary in 2005.

Disorders of purines and pyrimidines.

Disorders of purine and pyrimidine metabolism can result in an array of clinical manifestations including neurologic manifestations. The most commonly cited disorder, in the neurologic realm, is Lesch-Nyhan syndrome which presumably reflects its distinctive feature of self-mutilation. Expansion of our knowledge with molecular genetic methodology has helped to better identify and characterize mutations such as those which occur with the enzyme hypoxanthine guanine phosphoribosyltransferase (HPRT), and this has enhanced our understanding of phenotypical expression of Lesch-Nyhan syndrome and Lesch-Nyhan variants. It is hoped that further elucidation of DNA coding regions and messenger RNA expression will lead to the potential for gene therapy to correct these inborn errors of purine and pyrimidine metabolism.

Enfermedad de vnn gierke: nuevas tendencias en el manejo / Von gieke diseasse: new trends in management / Doença de vn gieerke: novas tendências no tratamento

La enfermedad de von Gierke, también conocida como enfermedad de deposito de glucógeno tipo Ia, es una enfermedad producida por la deficiencia de la unidad catalítica de la G6Pasa-a, encargada de hidrolizar la glucosa 6 fosfato en el citoplasma celular durante la gluconeogénesis y la glucogenolisis. Las complicaciones a largo plazo son hipoglicemia severa y alteraciones en el crecimiento. En los niños más pequeños la enfermedad típicamente se presenta con crisis convulsivas y hepatomegalia que se manifiestan a los 6 y 8 meses. Otras complicaciones son osteoporosis, gota, enfermedad renal, hipertensión pulmonar y adenomas hepáticos que pueden malignizarse. No se ha encontrado una cura y de no recibir un manejo adecuado es letal en las primeras dos décadas de la vida. El tratamiento consiste en terapia nutricional, asociada a varios medicamentos convencionales. Algunos pacientes pueden requerir transplante renal o transplante hepático. Una nueva esperanza se ha abierto con el advenimiento de la terapia génica con vectores virales, esta estrategia hasta ahora esta siendo desarrollada, pero los estudios realizados han mostrado una luz de esperanza para investigadores, médicos y pacientes. Faltan estudios para que estos tratamientos permitan un beneficio a largo plazo y su aplicación en humanos, ya que las pruebas como es de esperarse solo han sido desarrolladas en modelos animales.

Von Gierke disease, also known as glycogen storage disease type Ia, is a disease caused by deficiency of the G6Pase-a catalytic unit, which hydrolyzes glucose-6- phosphate in the cell cytoplasm during gluconeogenesis and glycogenolysis. Long term complications include severe hypoglycemia and growth disturbances. In small children, the disease typically presents with seizure crisis and hepatomegaly which become manifest at the age of 6 and 8 months. Other complications include osteoporosis, gout, renal disease, pulmonary hypertension and hepatic adenomas which can become malignant. No cure has been found for this disease and it can turn out to be lethal if no appropriate management is given during the first two decades of life. The treatment consists of nutritional therapy associated with a number of conventional drugs. Some patients may require renal or liver transplant. A new hope has emerged with the arrival of gene therapy with viral vectors, strategy that is being developed hitherto, yet performed studies have shown a glimmer of hope for investigators, doctors and patients. There is a need for studies so these treatments allow for a longer term benefit and their application in humans since, as expected, the tests have been developed only in animal models.

A doença de Von Gierke, também conhecida como Glicogenose tipo I, é uma doença produzida pela deficiência da unidade catalítica da G6Pasa-a, encarregada de hidrolisar a glicose 6 fosfato no citoplasma celular durante a gliconeogênese e a glicogenólise. As complicações a longo prazo são hipoglicemia severa e alterações no crescimento. Nas crianças menores a doença se apresenta tipicamente com crises convulsivas e hepatomegalia que se manifestam aos 6 e 8 meses. Outras complicações são osteoporose, gota, doença renal, hipertensão pulmonar e adenomas hepáticos que podem malignizar-se. Não foi encontrada uma cura e se não recebe tratamento adequado é letal nas primeiras duas décadas de vida. O tratamento consiste em terapia nutricional, associada a vários medicamentos convencionais. Alguns pacientes podem requerer transplante renal ou transplante hepático. Uma nova esperança apareceu com a terapia gênica com vetores virais, esta estratégia até agora esta sendo desenvolvida, mas os estudos realizados mostram uma luz de esperança para pesquisadores, médicos e pacientes. Faltam estudos para que estes tratamentos permitam um beneficio a longo prazo e a sua aplicação em humanos, já que os testes como é de se esperar só foram desenvolvidos em modelos animais.

CT scan diagnosis of hepatic adenoma in a case of von Gierke disease.

Hepatic adenoma is a well-defined, benign, solitary tumor of the liver. In individuals with glycogen storage disease I, adenoma tends to occur at a relatively younger age and can be multiple (adenomatosis). Imaging plays a pivotal role in diagnosing hepatic adenoma and in differentiating adenoma from other focal hepatic lesions. Especially in patients with von Gierke disease, in addition to the associated hepatomegaly caused by steatohepatitis and the diffusely reduced attenuation of the liver parenchyma seen on CT, there may be more than one hepatic adenoma in up to 40% of patients. Malignant degeneration of hepatic adenoma into hepatocellular carcinoma can occur and hence imaging is important for prompt diagnosis of adenoma and its complications. In this case report, we present a case of liver adenoma diagnosed by CT scan in a patient with von Gierke disease.

A Case of von Gierke Disease

von Gierke disease (type Ia glycogen storage disease) is an inherited disease associated with accumulation of glycogen in the liver, kidney, intestine and erythrocytes due to the defect of glucose-6-phosphatase activity. Hepatomegaly, doll face, anemia, bleeding tendency and increased susceptability to infection are common features observed during infancy. Hypoglycemia especially fasting hypoglycemia is typical metabolic derangement in this disease, followed by metabolic acidosis, lactic acidemia, hyperlipidemia, hyperuricemia, and platelets dysfunction. We experienced a case of von Gierke disease in 6 month-old boy with doll face, hepatomegaly, fasting hypoglycemia, acidosis, anemia, hyperlipidemia, hyperuricemia, and acetonuria. Diagnosis was confirmed by light- and electron microscopic examination of liver biopsy specimen, which revealed hepatocytes filled with dense pools of glycogen and many lipid droplets. Cornstarch dietary therapy for him had favorable responses showing improvement of hypoglycemia, other metabolic derangements, and regression of hepatomegaly.

A Case of von Gierke Disease

von Gierke disease (type Ia glycogen storage disease) is an inherited disease associated with accumulation of glycogen in the liver, kidney, intestine and erythrocytes due to the defect of glucose-6-phosphatase activity. Hepatomegaly, doll face, anemia, bleeding tendency and increased susceptability to infection are common features observed during infancy. Hypoglycemia especially fasting hypoglycemia is typical metabolic derangement in this disease, followed by metabolic acidosis, lactic acidemia, hyperlipidemia, hyperuricemia, and platelets dysfunction. We experienced a case of von Gierke disease in 6 month-old boy with doll face, hepatomegaly, fasting hypoglycemia, acidosis, anemia, hyperlipidemia, hyperuricemia, and acetonuria. Diagnosis was confirmed by light- and electron microscopic examination of liver biopsy specimen, which revealed hepatocytes filled with dense pools of glycogen and many lipid droplets. Cornstarch dietary therapy for him had favorable responses showing improvement of hypoglycemia, other metabolic derangements, and regression of hepatomegaly.