Glycogen Storage Disease Type 1a Research Articles

Diabetes in a Patient with Glycogen Storage Disease Type 1a.

Glycogen storage disease type 1a (GSD-1a) is a rare congenital disease. Recently, life expectancy with GSD-1a has been improved by its early diagnosis and management. Complications of diabetes with GSD-1a are extremely rare. The optimal treatment for glucose control using this disease combination remains unclear. The existence of GSD-1a and diabetes can cause both hypoglycemia and hyperglycemia, making glucose control especially problematic. In the present report, α-glucosidase inhibitor (α-GI) and dipeptidyl peptidase-4 (DPP-4) inhibitors improved hyperglycemia without symptoms of hypoglycemia in a patient with diabetes and GSD-1a using intermittent continuous glucose monitoring (isCGM).

A splice-switching oligonucleotide treatment ameliorates glycogen storage disease type 1a in mice with G6PC c.648G>T.

Glycogen storage disease type 1a (GSD1a) is caused by a congenital deficiency of glucose-6-phosphatase-α (G6Pase-α, encoded by G6PC), which is primarily associated with life-threatening hypoglycemia. Although strict dietary management substantially improves life expectancy, patients still experience intermittent hypoglycemia and develop hepatic complications. Emerging therapies utilizing new modalities such as adeno-associated virus and mRNA with lipid nanoparticles are under development for GSD1a but potentially require complicated glycemic management throughout life. Here, we present an oligonucleotide-based therapy to produce intact G6Pase-α from a pathogenic human variant, G6PC c.648G>T, the most prevalent variant in East Asia causing aberrant splicing of G6PC. DS-4108b, a splice-switching oligonucleotide, was designed to correct this aberrant splicing, especially in liver. We generated a mouse strain with homozygous knockin of this variant that well reflected the pathophysiology of patients with GSD1a. DS-4108b recovered hepatic G6Pase activity through splicing correction and prevented hypoglycemia and various hepatic abnormalities in the mice. Moreover, DS-4108b had long-lasting efficacy of more than 12 weeks in mice that received a single dose and had favorable pharmacokinetics and tolerability in mice and monkeys. These findings together indicate that this oligonucleotide-based therapy could provide a sustainable and curative therapeutic option under easy disease management for GSD1a patients with G6PC c.648G>T.

Long-Term Treatment of Lipoprotein Lipase Deficiency with Medium-Chain Triglyceride-Enriched Diet: A Case Series.

Background: Lipoprotein lipase (LPL) deficiency is a genetic condition. Affected individuals typically develop symptoms related to severe and persistent hypertriglyceridemia, such as abdominal pain and recurrent pancreatitis, before 10 years of age. No pharmacological treatment sustainably lowering triglycerides (TGs) in LPL deficiency patients has been proven to be effective. This study investigated whether a long-chain triglyceride (LCT)-restricted, medium-chain triglyceride (MCT)-supplemented diet enables a meaningful reduction in TGs and reduces LPL-related symptoms in children with LPL deficiency. Methods: A single-center retrospective case series study of LPL deficiency patients treated at the Hospital of Sick Children between January 2000 and December 2022 was carried out. Data, extracted from hospital charts, included demographics, diagnosis confirmation, clinical and imaging observations, and biochemical profiles. Results: Seven patients with hypertriglyceridemia > 20 mmol/L suspected of an LPL deficiency diagnosis were included. Six patients had a confirmed molecular diagnosis of LPL deficiency, and one had glycogen storage disease type 1a (GSD1a). Clinical presentation was at a median of 30 days of age (range 1-105), and treatment start, excluding one late-treated patient, was at a median of 42 days (range 2-106). The observation and treatment period of the LPL patients was 48.0 patient years (median 7.1, range 4.3-15.5). The LCT-restricted and MCT-supplemented diet led to an immediate drop in TGs in six out of six LPL patients. TGs improved from a median of 40.9 mmol/L (range 11.4-276.5) pre-treatment to a median of 12.0 mmol/L (range 1.1-36.6) during treatment, total cholesterol from 7.6 mmol/L (4.9-27.0) to 3.9 mmol/L (1.7-8.2), and pancreatic lipase from 631 IU/L (30-1200) to 26.5 IU/L (5-289). In 48 patient years, there was only one complication of pancreatitis and no other disease-specific manifestations or complications. Catch-up growth was observed in one late-treated patient. All patients maintained normal growth and development. As expected, the diet failed to treat hypertriglyceridemia in the GSD1a patient. Conclusions: The dietary restriction of LCT in combination with MCT supplementation as long-term management of pediatric patients with LPL deficiency was feasible, well tolerated, and clinically effective in reducing TG levels and in preventing LPL-related complications.

Report of an Iranian child with developmental motor delay and renal and hepatic complications diagnosed as a Glycogen storage disease type 1a: A case report

Background: Glycogen storage disease type 1a (GSD-1a) is the most common form of GSDs, accounting for 80% of these cases. Here we present a 16-month-old boy being treated for GSD-1a at our clinic. Case presentation: Given that the patient was not examined and diagnosed prior to referral to our clinic, mitochondrial disease due to developmental delay, high lactate levels, and lack of hypoglycemia was treated first. Given the fact that the patient’s clinical presentation could not be justified by repeat testing, DNA analysis showed evidence in favor of glucose-6-phosphatase deficiency. The result of the genetic analysis reported a known mutation of c.G193C (P.A65P). Conclusion: Because of the prevalence of this disease, GSD-1a should be considered in children with unexplained hypoglycemia and/or hepatomegaly. Proper metabolic control and prohibition of hypoglycemia should aim to reach the desired point.

Anesthetic Management of a Glycogen Storage Disease Type 1a with Air Embolism During Liver Transplantation: A Case Report

Anesthetic Management of a Glycogen Storage Disease Type 1a with Air Embolism During Liver Transplantation: A Case Report

Molecular, Biochemical, and Clinical Characterization of Thirteen Patients with Glycogen Storage Disease 1a in Malaysia.

Background Glycogen storage disease type 1a (GSD1a) is a rare autosomal recessive metabolic disorder characterized by hypoglycaemia, growth retardation, lactic acidosis, hepatomegaly, hyperlipidemia, and nephromegaly. GSD1a is caused by a mutation in the G6PC gene encoding glucose-6-phosphatase (G6Pase); an enzyme that catalyses the hydrolysis of glucose-6-phosphate (G6P) to phosphate and glucose. Objective To elaborate on the clinical findings, biochemical data, molecular genetic analysis, and short-term prognosis of 13 GSD1a patients in Malaysia. Methods The information about 13 clinically classified GSD1a patients was retrospectively studied. The G6PC mutation analysis was performed by PCR-DNA sequencing. Results Patients were presented with hepatomegaly (92%), hypoglycaemia (38%), poor weight gain (23%), and short stature (15%). Mutation analysis revealed nine heterozygous mutations; eight previously reported mutations (c.155 A > T, c.209 G > A, c.226 A > T, c.248 G > A, c.648 G > T, c.706 T > A, c.1022 T > A, c.262delG) and a novel mutation (c.325 T > C). The most common mutation found in Malaysian patients was c.648 G > T in ten patients (77%) of mostly Malay ethnicity, followed by c.248 G > A in 4 patients of Chinese ethnicity (30%). A novel missense mutation (c.325 T > C) was predicted to be disease-causing by various in silico software. Conclusions The establishment of G6PC molecular genetic testing will enable the detection of presymptomatic patients, assisting in genetic counselling while avoiding the invasive methods of liver biopsy.

Glycogen storage disease type 1a in the Ohio Amish.

Glycogen storage disease type 1a (GSD1a) is an inborn error of glucose metabolism characterized by fasting hypoglycemia, hepatomegaly, and growth failure. Late complications include nephropathy and hepatic adenomas. We conducted a retrospective observational study on a cohort of Amish patients with GSD1a. A total of 15 patients cared for at a single center, with a median age of 9.9 years (range 0.25–24 years) were included. All patients shared the same founder variant in GCPC c.1039 C > T. The phenotype of this cohort demonstrated good metabolic control with median cohort triglyceride level slightly above normal, no need for continuous overnight feeds, and a higher quality of life compared to a previous GSD cohort. The most frequent complications were oral aversion, gross motor delay, and renal hyperfiltration. We discuss our unique care delivery at a single center that cares for Amish patients with inherited disorders.

Serum sex hormone-binding globulin levels are reduced and inversely associated with intrahepatic lipid content and saturated fatty acid fraction in adult patients with glycogen storage disease type 1a

PurposeDe novo lipogenesis has been inversely associated with serum sex hormone-binding globulin (SHBG) levels. However, the directionality of this association has remained uncertain. We, therefore, studied individuals with glycogen storage disease type 1a (GSD1a), who are characterized by a genetic defect in glucose-6-phosphatase resulting in increased rates of de novo lipogenesis, to assess the downstream effect on serum SHBG levels.MethodsA case–control study comparing serum SHBG levels in patients with GSD1a (n = 10) and controls matched for age, sex, and BMI (n = 10). Intrahepatic lipid content and saturated fatty acid fraction were quantified by proton magnetic resonance spectroscopy.ResultsSerum SHBG levels were statistically significantly lower in patients with GSD1a compared to the controls (p = 0.041), while intrahepatic lipid content and intrahepatic saturated fatty acid fraction—a marker of de novo lipogenesis—were significantly higher in patients with GSD1a (p = 0.001 and p = 0.019, respectively). In addition, there was a statistically significant, inverse association of intrahepatic lipid content and saturated fatty acid fraction with serum SHBG levels in patients and controls combined (β: − 0.28, 95% CI: − 0.47;− 0.09 and β: − 0.02, 95% CI: − 0.04;− 0.01, respectively).ConclusionPatients with GSD1a, who are characterized by genetically determined higher rates of de novo lipogenesis, have lower serum SHBG levels than controls.

Modeling Phenotypic Heterogeneity of Glycogen Storage Disease Type 1a Liver Disease in Mice by Somatic CRISPR/CRISPR-associated protein 9-Mediated Gene Editing.

Background and AimsPatients with glycogen storage disease type 1a (GSD‐1a) primarily present with life‐threatening hypoglycemia and display severe liver disease characterized by hepatomegaly. Despite strict dietary management, long‐term complications still occur, such as liver tumor development. Variations in residual glucose‐6‐phosphatase (G6PC1) activity likely contribute to phenotypic heterogeneity in biochemical symptoms and complications between patients. However, lack of insight into the relationship between G6PC1 activity and symptoms/complications and poor understanding of the underlying disease mechanisms pose major challenges to provide optimal health care and quality of life for GSD‐1a patients. Currently available GSD‐1a animal models are not suitable to systematically investigate the relationship between hepatic G6PC activity and phenotypic heterogeneity or the contribution of gene‐gene interactions (GGIs) in the liver.Approach and ResultsTo meet these needs, we generated and characterized a hepatocyte‐specific GSD‐1a mouse model using somatic CRISPR/CRISPR‐associated protein 9 (Cas9)–mediated gene editing. Hepatic G6pc editing reduced hepatic G6PC activity up to 98% and resulted in failure to thrive, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly, hepatic steatosis (HS), and increased liver tumor incidence. This approach was furthermore successful in simultaneously modulating hepatic G6PC and carbohydrate response element‐binding protein, a transcription factor that is activated in GSD‐1a and protects against HS under these conditions. Importantly, it also allowed for the modeling of a spectrum of GSD‐1a phenotypes in terms of hepatic G6PC activity, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly and HS.ConclusionsIn conclusion, we show that somatic CRISPR/Cas9‐mediated gene editing allows for the modeling of a spectrum of hepatocyte‐borne GSD‐1a disease symptoms in mice and to efficiently study GGIs in the liver. This approach opens perspectives for translational research and will likely contribute to personalized treatments for GSD‐1a and other genetic liver diseases.

A Case of Glycogen Storage Disease Type 1a Mimicking Familial Chylomicronemia Syndrome.

Glycogen storage disease type 1a (GSD1a) is an autosomal recessively inherited inborn error of metabolism caused by a mutation in the G6PC gene, which encodes the catalytic subunit of glucose-6-phosphatase-α (G6Pase-α) enzyme. This enzyme plays a role in the final step of gluconeogenesis and glycogenolysis. Patients carrying GSD1a show growth retardation, hypoglycemia, hepatomegaly, hepatic steatosis, hyperlipidemia, hyperuricemia and lactic acidemia. Long-term symptoms include gouty arthritis and uric acid stones, osteoporosis, renal failure, intestinal impairment, cirrhosis and hepatic adenomas, and eventually, hepatocellular carcinoma. Hyperlipidemia is the indicator of poor metabolic control in GSD1a. Patients with variable levels of triglycerides (TGs) have been reported in the literature. We present a case of GSD1a that presented with severe hypertriglyceridemia (HTG) mimicking familial chylomicronemia syndrome.

Classifying molecular phenotypes of G6PC variants for pathogenic properties and to guide therapeutic development.

Due to advances in sequencing technologies, identification of genetic variants is rapid. However, the functional consequences of most genomic variants remain unknown. Consequently, variants of uncertain significance (VUS) that appear in clinical DNA diagnostic reports lack sufficient data for interpretation. Algorithms exist to aid prediction of a variant's likelihood of pathogenicity, but these predictions usually lack empiric evidence. To examine the feasibility of generating functional evidence in vitro for a given variant's role in disease, a panel of 29 coding sequence variants in the G6PC gene was assessed. G6PC encodes glucose‐6 phosphatase enzyme, and reduction in its function causes the rare metabolic disease glycogen storage disease type 1a (GSD1a). Variants were heterologously expressed as fusion proteins in a hepatocyte‐derived cell line and examined for effects on steady‐state protein levels, biosynthetic processing, and intracellular distribution. The screen revealed variant effects on protein levels, N‐linked glycosylation status, and cellular distribution. Of the eight VUS tested, seven behaved similar to wild‐type protein while one VUS, p.Cys109Tyr, exhibited features consistent with pathogenicity for all molecular phenotypes assayed, including significantly reduced protein levels, alteration in protein glycosylation status, and abnormally diffuse protein localization pattern, and has recently been reported in a patient with GSD1a. Our results show that such a screen can add empiric evidence to existing databases to aid in diagnostics, and also provides further classification for molecular phenotypes that could be used in future therapeutic screening approaches for small molecule or gene editing strategies directed at specific variants.

NOVEL MUTATIONS OF THE G6PC GENE IN MALAYSIANS WITH GLYCOGEN STORAGE DISEASE 1a (GSD1a)

Abstract Glycogen Storage Disease 1a is a rare autosomal recessive disorder caused by mutations in the glucose-6-phosphatase gene (G6PC) encoding glucose-6-phosphatase (G6Pase), a key enzyme for the maintenance of glucose homeostasis. Deficiency of G6Pase underlies this disease associated with life-threatening hypoglycemia and growth retardation. To date, more than 110 mutations have be found worldwide.The aims of this study are to identify the mutations in G6PC gene in Malaysian GSD1a patients using standard molecular genetics methods and to determine the pathogenicity level of the novel mutations. We performed mutation screening for 21 GSD1a unrelated patients (Malay n=14; Chinese n=7) using Polymerase Chain Reaction (PCR) and DNA sequencing. Genomic DNA was extracted from patients’ peripheral blood and all five G6PC exons were amplified using specific primers. Nine mutations were found, in which five mutations have been previously reported and four are potentially novel mutations (H52L, K76X, P113S and A346P). To obtain further evidence on the potential pathogenicity of the novel mutations, restriction enzyme assay and TaqMan genotyping assay were designed to investigate its allele frequency in a panel of healthy individuals that serves as the control population samples (n=50 Malays, n=50 Chinese, n=50 Indians). Restriction enzymes MseI and MboI were used to assay the K76X and P113S mutations respectively. For the other two mutations (H52L and A346P), TaqMan genotyping assays was employed due to inavailability of a suitable restriction enzyme to distinguish between the normal and mutant sequences. Results obtained from both the restriction enzymes assays and the TaqMan assays showed that no mutant allele could be found in all 150 healthy individuals (300 alleles). In conclusion, four yet unreported mutations have been found in the Malaysian population, and these mutations are potentially novel pathogenic mutations. These finding provide support that the mutations spectrum of G6PC gene in Malaysia is heterogeneous, at least among the Chinese and Malay populations. KEY WORDS: Glycogen storage disease type 1a (GSD1a); glucose-6-phosphatase enzyme (G6Pase); Glucose-6-Phosphate catalytic subunit (G6PC).

Generation of a human induced pluripotent stem cell line, BRCi009-A, derived from a patient with glycogen storage disease type 1a.

Glycogen storage disease type 1a (GSD1a) is an autosomal recessive disorder caused by mutations of the glucose-6-phosphatase (G6PC) gene. Mutations of the G6PC gene lead to excessive accumulation of glycogen in the liver, kidney, and intestinal mucosa due to the deficiency of microsomal glucose-6-phosphatase. Human induced pluripotent stem cells (iPSCs) enable the production of patient-derived hepatocytes in culture and are therefore a promising tool for modeling GSD1a. Here, we report the establishment of human iPSCs from a GSD1a patient carrying a G6PC mutation (c.648G > T; p.Leu216 = ).

Circulating exosomal microRNAs as potential biomarkers of hepatic injury and inflammation in a murine model of glycogen storage disease type 1a.

ABSTRACTMost patients affected by glycogen storage disease type 1a (GSD1a), an inherited metabolic disorder caused by mutations in the enzyme glucose-6-phosphatase-α (G6Pase-α), develop renal and liver complications, including the development of hepatocellular adenoma/carcinoma. The purpose of this study was to identify potential biomarkers of the pathophysiology of the GSD1a-affected liver. To this end, we used the plasma exosomes of a murine model of GSD1a, the LS-G6pc−/− mouse, to uncover the modulation in microRNA expression associated with the disease. The microRNAs differentially expressed between LS-G6pc−/− and wild-type mice, LS-G6pc−/− mice with hepatocellular adenoma and LS-G6pc−/− mice without adenoma, and LS-G6pc−/− mice with amyloidosis and LS-G6pc−/− mice without amyloidosis were identified. Pathway analysis demonstrated that the target genes of the differentially expressed microRNA were significantly enriched for the insulin signaling pathway, glucose and lipid metabolism, Wnt/β-catenin, telomere maintenance and hepatocellular carcinoma, and chemokine and immune regulation signaling pathways. Although some microRNAs were common to the different pathologic conditions, others were unique to the cancerous or inflammatory status of the animals. Therefore, the altered expression of several microRNAs is correlated with various pathologic liver states and might help to distinguish them during the progression of the disease and the development of late GSD1a-associated complications.

A Proteomic Analysis of GSD-1a in Mouse Livers: Evidence for Metabolic Reprogramming, Inflammation, and Macrophage Polarization.

Glycogen storage disease type 1a (GSD-1a) is a rare genetic disease caused by mutations in the catalytic subunit of the enzyme glucose-6-phosphatase-alpha (G6Pase-α). The majority of patients develop long-term complications including renal failure and hepatocellular adenoma/carcinoma. The purpose of this study was to ascertain the proteomic changes in the liver of LS- G6pc-/- mice, a murine model of GSD-1a, in comparison with wild type mice to identify potential biomarkers of the pathophysiology of the affected liver. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze liver lysates from a total of 20 LS- G6pc-/- and 18 wild type (WT) mice. We compared the proteomic expression profile of LS- G6pc-/- and WT mice. We identified 4138 significantly expressed proteins, 1243 of which were differentially represented. Network and pathway analyses indicate that LS- G6pc-/- livers display an age-dependent modulation of the expression of proteins involved in specific biological processes associated with increased progression of liver disease. Moreover, we found upregulation of proteins involved in the process of tissue inflammation and macrophage polarization toward the M2 phenotype in LS- G6pc-/- mice with adenomas. Our results identify a metabolic reprogramming of glucose-6-P and a pathologic environment in the liver compatible with tumor development and progression.

Anaesthetic Management of a Patient with Glycogen Storage Disease Type 1A

Glycogen storage diseases (GSD) are a group of inherited disorders which result in deficiencies of enzymes involved in glycogen metabolism and lead to an accumulation of glycogen in the liver. Glycogen storage disease type 1a, a form of glycogen storage disturbance, is a rare metabolic disorder with important implications for anaesthesiologists. It is caused by the lack of the glucose-6-phosphatase, which is necessary for the liver to convert glycogen to glucose. The aim of this case report is to present an uncomplicated surgery with an uncomplicated general anaesthesia and an anaesthetic follow up in a patient with GSD type 1a in an elective day case surgery. In this case, there was a serious hypoglycemia problem due to the glycogen storage disturbance related to disease. To avoid severe hypoglycemia, it is crucial to keep oral feeding 2-3 hour for maintaining a normal blood sugar level.

You Are Never Too Old: A Case of Glycogen Storage Disease Type 1 in an Adult: 2017 Presidential Poster Award

Glycogen storage disease (GSD) type 1a, also known as Von Gierke's disease, is caused by the absence of glucose-6-dephosphatase. This disease usually manifests in infancy with hypoglycemia, hepatomegaly, and poor growth. In rare cases, adults have been diagnosed with GSD type 1a usually by the presence of hepatocellular adenomas. A 40-year-old Hispanic man presented initially after motor vehicle accident due to a seizure. CT abdomen was performed with an incidental finding of a liver mass, which was biopsied multiple times and showed hepatic adenoma. For two years after this initial presentation, he had multiple hospitalizations for abdominal pain due to ruptured hepatic adenomas, with resultant bleeding requiring embolization. He was diagnosed with GSD type 1 based on clinical features including hepatomegaly, seizures, stunted growth, and normal spleen size. This diagnosis was confirmed, prior to his sixth embolization for ruptured adenoma, with genetic testing which showed 2 copies of pathogenic variant G6PC gene detected (c. 113A>T). On physical exam, he was found to have a protuberant abdomen with hepatomegaly, short stature, thin limbs, and subcutaneous nodules consistent with tophi. CT abdomen showed multiple adenomas, the largest measuring 7 x 7 cm in the caudate lobe. Liver tests showed ALT 46 U/L, AST 43 U/L, ALP 456 U/L, bilirubin 0.3 mg/dL. He has undergone serial imaging to evaluate for change in liver lesion size as adenoma transformation to hepatocellular carcinoma has been described. Nutrition consult was obtained as dietary modification to promote optimal metabolic control has been described in younger patients with smaller lesions. Liver transplantation was discussed as patient had large, multiple adenomas with bleeding. GSD type 1a, usually a pediatric diagnosis, can uncommonly be seen in adults. To date, there are only two reported cases of patients with a later diagnosis in adulthood, typically found in patients with mild disease. A presentation of adenomatosis without previous known GSD type 1a can occur and should prompt further evaluation for this genetic mutation even in adults, especially if other features are suggestive of this genetic disorder.Figure: Multiple adenomas seen on sagittal view of CT abdomen.Figure: Hepatomegaly and multiple adenomas on coronal view of CT abdomen.

Calcium as a marker of metabolic decompensation in glycogen storage disease type-1a

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Hepatic lentiviral gene transfer prevents the long-term onset of hepatic tumours of glycogen storage disease type 1a in mice.

Glycogen storage disease type 1a (GSD1a) is a rare disease due to the deficiency in the glucose-6-phosphatase (G6Pase) catalytic subunit (encoded by G6pc), which is essential for endogenous glucose production. Despite strict diet control to maintain blood glucose, patients with GSD1a develop hepatomegaly, steatosis and then hepatocellular adenomas (HCA), which can undergo malignant transformation. Recently, gene therapy has attracted attention as a potential treatment for GSD1a. In order to maintain long-term transgene expression, we developed an HIV-based vector, which allowed us to specifically express the human G6PC cDNA in the liver. We analysed the efficiency of this lentiviral vector in the prevention of the development of the hepatic disease in an original GSD1a mouse model, which exhibits G6Pase deficiency exclusively in the liver (L-G6pc(-/-) mice). Recombinant lentivirus were injected in B6.G6pc(ex3lox/ex3lox). SA(creERT2/w) neonates and G6pc deletion was induced by tamoxifen treatment at weaning. Magnetic resonance imaging was then performed to follow up the development of hepatic tumours. Lentiviral gene therapy restored glucose-6 phosphatase activity sufficient to correct fasting hypoglycaemia during 9 months. Moreover, lentivirus-treated L-G6pc(-/-) mice presented normal hepatic triglyceride levels, whereas untreated mice developed steatosis. Glycogen stores were also decreased although liver weight remained high. Interestingly, lentivirus-treated L-G6pc(-/-) mice were protected against the development of hepatic tumours after 9 months of gene therapy while most of untreated L-G6pc(-/-) mice developed millimetric HCA. Thus the treatment of newborns by recombinant lentivirus appears as an attractive approach to protect the liver from the development of steatosis and hepatic tumours associated to GSD1a pathology.

Development of hepatocellular adenomas and carcinomas in mice with liver-specific G6Pase-α deficiency.

Glycogen storage disease type 1a (GSD-1a) is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α), and is characterized by impaired glucose homeostasis and a high risk of developing hepatocellular adenomas (HCAs). A globally G6Pase-α-deficient (G6pc−/−) mouse model that shows pathological features similar to those of humans with GSD-1a has been developed. These mice show a very severe phenotype of disturbed glucose homeostasis and rarely live beyond weaning. We generated liver-specific G6Pase-α-deficient (LS‑G6pc−/−) mice as an alternative animal model for studying the long-term pathophysiology of the liver and the potential treatment strategies, such as cell therapy. LS‑G6pc−/− mice were viable and exhibited normal glucose profiles in the fed state, but showed significantly lower blood glucose levels than their control littermates after 6 hours of fasting. LS‑G6pc−/− mice developed hepatomegaly with glycogen accumulation and hepatic steatosis, and progressive hepatic degeneration. Ninety percent of the mice analyzed developed amyloidosis by 12 months of age. Finally, 25% of the mice sacrificed at age 10–20 months showed the presence of multiple HCAs and in one case late development of hepatocellular carcinoma (HCC). In conclusion, LS‑G6pc−/− mice manifest hepatic symptoms similar to those of human GSD-1a and, therefore, represent a valid model to evaluate long-term liver pathogenesis of GSD-1a.