A Mouse Model of Glycogen Storage Disease Type IX-Beta: A Role for Phkb in Glycogenolysis.

Glycogen storage disease type IX (GSD-IX) constitutes nearly a quarter of all GSDs. This ketotic form of GSD is caused by mutations in phosphorylase kinase (PhK), which is composed of four subunits (α, ß, γ, δ). PhK is required for the activation of the liver isoform of glycogen phosphorylase (PYGL), which generates free glucose-1-phosphate monomers to be used as energy via cleavage of the α -(1,4) glycosidic linkages in glycogen chains. Mutations in any of the PhK subunits can negatively affect the regulatory and catalytic activity of PhK during glycogenolysis. To understand the pathogenesis of GSD-IX-beta, we characterized a newly created PHKB knockout (Phkb−/−) mouse model. In this study, we assessed fasting blood glucose and ketone levels, serum metabolite concentrations, glycogen phosphorylase activity, and gene expression of gluconeogenic genes and fibrotic genes. Phkb−/− mice displayed hepatomegaly with lower fasting blood glucose concentrations. Phkb−/− mice showed partial liver glycogen phosphorylase activity and increased sensitivity to pyruvate, indicative of partial glycogenolytic activity and upregulation of gluconeogenesis. Additionally, gene expression analysis demonstrated increased lipid metabolism in Phkb−/− mice. Gene expression analysis and liver histology in the livers of old Phkb−/− mice (>40 weeks) showed minimal profibrogenic features when analyzed with age-matched wild-type (WT) mice. Collectively, the Phkb−/− mouse recapitulates mild clinical features in patients with GSD-IX-beta. Metabolic and molecular analysis confirmed that Phkb−/− mice were capable of sustaining energy homeostasis during prolonged fasting by using partial glycogenolysis, increased gluconeogenesis, and potentially fatty acid oxidation in the liver.

Emerging roles of autophagy in hepatic tumorigenesis and therapeutic strategies in glycogen storage disease type Ia: A review.

Glycogen storage disease type Ia (GSD-Ia) is an inherited metabolic disease caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC) which plays a critical role in blood glucose homeostasis by catalyzing the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate in the terminal step of glycogenolysis and gluconeogenesis. Patients with GSD-Ia manifest life-threatening fasting hypoglycemia along with the excessive accumulation of hepatic glycogen and triglycerides which results in hepatomegaly and a risk of long-term complications such as hepatocellular adenoma and carcinoma (HCA/HCC). The etiology of HCA/HCC development in GSD-Ia, however, is unknown. Recent studies have shown that the livers in model animals of GSD-Ia display impairment of autophagy, a cellular recycling process which is critical for energy metabolism and cellular homeostasis. However, molecular mechanisms of autophagy impairment and its involvement in pathogenesis in GSD-Ia are still under investigation. Here, we summarize the latest advances for signaling pathways implicated in hepatic autophagy impairment and the roles of autophagy in hepatic tumorigenesis in GSD-Ia. In addition, recent evidence has illustrated that autophagy plays an important role in hepatic metabolism and liver-directed gene therapy mediated by recombinant adeno-associated virus (rAAV). Therefore, we highlight the possible role of hepatic autophagy in metabolic control and rAAV-mediated gene therapy for GSD-Ia. In this review, we also provide potential therapeutic strategies for GSD-Ia on the basis of molecular mechanisms underlying hepatic autophagy impairment in GSD-Ia.

The potential of dietary treatment in patients with glycogen storage disease type IV.

There is paucity of literature on dietary treatment in glycogen storage disease (GSD) type IV and formal guidelines are not available. Traditionally, liver transplantation was considered the only treatment option for GSD IV. In light of the success of dietary treatment for the other hepatic forms of GSD, we have initiated this observational study to assess the outcomes of medical diets, which limit the accumulation of glycogen. Clinical, dietary, laboratory, and imaging data for 15 GSD IV patients from three centres are presented. Medical diets may have the potential to delay or prevent liver transplantation, improve growth and normalize serum aminotransferases. Individual care plans aim to avoid both hyperglycaemia, hypoglycaemia and/or hyperketosis, to minimize glycogen accumulation and catabolism, respectively. Multidisciplinary monitoring includes balancing between traditional markers of metabolic control (ie, growth, liver size, serum aminotransferases, glucose homeostasis, lactate, and ketones), liver function (ie, synthesis, bile flow and detoxification of protein), and symptoms and signs of portal hypertension.

Exosomal MicroRNAs as Potential Biomarkers of Hepatic Injury and Kidney Disease in Glycogen Storage Disease Type Ia Patients.

Glycogen storage disease type Ia (GSDIa) is an inherited metabolic disorder caused by mutations in the enzyme glucose-6-phosphatase-α (G6Pase-α). Affected individuals develop renal and liver complications, including the development of hepatocellular adenoma/carcinoma and kidney failure. The purpose of this study was to identify potential biomarkers of the evolution of the disease in GSDIa patients. To this end, we analyzed the expression of exosomal microRNAs (Exo-miRs) in the plasma exosomes of 45 patients aged 6 to 63 years. Plasma from age-matched normal individuals were used as controls. We found that the altered expression of several Exo-miRs correlates with the pathologic state of the patients and might help to monitor the progression of the disease and the development of late GSDIa-associated complications.

Glucose-6-phosphate transporter mediates macrophage proliferation and functions by regulating glycolysis and mitochondrial respiration.

Glycogen storage disease type Ib (GSD-Ib), caused by a deficiency in glucose-6-phosphate transporter (G6PT), is characterized by disrupted glucose homeostasis, inflammatory bowel disease, neutropenia, and neutrophil dysfunction. The purpose of this study was to investigate the role of G6PT on macrophage functions and metabolism. Peritoneal macrophages of G6pt-/- mice were lower in number and their effector functions including migration, superoxide production, and phagocytosis were impaired. To investigate the underlying mechanisms of macrophage dysfunction, the G6PT gene was mutated in porcine alveolar macrophage 3D4/31 cells using the CRISPR/Cas9 technology. The G6PT-deficient macrophages exhibited significant decline in cell growth, bactericidal activity, and antiviral response. These phenotypes are associated with the impaired glycolysis and mitochondrial oxidative phosphorylation. We therefore propose that the G6PT-mediated metabolism is essential for effector functions of macrophage, the immune deficiencies observed in GSD-Ib extend beyond neutropenia and neutrophil dysfunction, and future therapeutic targets aimed both the neutrophils and macrophages may be necessary.

Cornstarch requirements of the adult glycogen storage disease Ia population: A retrospective review.

Cornstarch has been the primary treatment for glycogen storage disease type Ia (GSD Ia) for over 35 years. When cornstarch was first described as a treatment, few people survived beyond early childhood. As the prognosis for this population has improved, the need to ensure appropriate cornstarch dosing for different age groups has become imperative. Records from 115 patients (10-62 years of age) with GSD Ia evaluated at our center between 2015 and 2017 were reviewed. Data collected included weight, age, genetic mutation, amount and frequency of cornstarch doses, body mass index, gender, 24-hour glucose and lactate concentrations, and biochemical markers of metabolic control. The data demonstrate that adult treatment needs vary greatly from younger age groups, and the required cornstarch support decreases with age (P < .001). The required number of doses, however, did not change with a mean of six doses (range 4-8) daily in all age groups. General laboratory findings across time demonstrate that significantly reducing the amount of starch required to maintain euglycemia with aging can be done without sacrificing metabolic control. Carbohydrate requirements decrease with aging, and older patients were found to require less cornstarch. Failure to lower the cornstarch doses contributes to over-treatment in adults with GSD Ia. Not only does this lead to worsening hepatomegaly and excessive weight gain, but over-treatment contributes to relative hyperinsulinism and rebound hypoglycemia. This knowledge is essential in designing nutritional therapies for the aging GSD population.

Research priorities for liver glycogen storage disease: An international priority setting partnership with the James Lind Alliance.

The international liver glycogen storage disease (GSD) priority setting partnership (IGSDPSP) was established to identify the top research priorities in this area. The multiphase methodology followed the principles of the James Lind Alliance (JLA) guidebook. An international scoping survey in seven languages was distributed to patients, carers, and healthcare professionals to gather uncertainties, which were consolidated into summary questions. The existing literature was reviewed to ensure that the summary questions had not yet been answered. A second survey asked responders to prioritize these summary questions. A final shortlist of 22 questions was discussed during an international multi-stakeholder workshop, and a consensus was reached on the top 11 priorities using an adapted nominal group technique.In the first survey, a total of 1388 questions were identified from 763 responders from 58 countries. These original uncertainties were refined into 72 summary questions for a second prioritization survey. In total 562 responders from 58 countries answered the second survey. From the second survey, the top 10 for patients, carers and healthcare professionals was identified and this shortlist of 22 questions was taken to the final workshop. During the final workshop, participants identified the worldwide top 11 research priorities for liver GSD. In addition, a top three research priorities per liver GSD subtype was identified.This unique priority setting partnership is the first international, multilingual priority setting partnership focusing on ultra-rare diseases. This process provides a valuable resource for researchers and funding agencies to foster interdisciplinary and transnational research projects with a clear benefit for patients.

Neutropenia in glycogen storage disease Ib: outcomes for patients treated with granulocyte colony-stimulating factor.

PURPOSE OF REVIEW: Glycogen storage disease Ib (GSD Ib) is characterized by hepatomegaly, hypoglycemia, neutropenia, enterocolitis and recurrent bacterial infections. It is attributable to mutations in G6PT1, the gene for the glucose-6-phosphate transporter responsible for transport of glucose into the endoplasmic reticulum. Neutropenia in GSD Ib is now frequently treated with granulocyte colony-stimulating factor (G-CSF). We formed a cooperative group to review outcomes of the long-term treatment of GSD Ib patients treated with G-CSF. RECENT FINDINGS: The study enrolled 103 patients (48 men and 55 women), including 47 currently adult patients. All of these patients were treated with G-CSF, starting at a median age of 3.8 years (range 0.04-33.9 years) with a median dose of 3.0 mcg/kg/day (range 0.01-93.1 mcg/kg/day) for a median of 10.3 years (range 0.01-29.3 years). Neutrophils increased in response to G-CSF in all patients (median values before G-CSF 0.2 × 10/l, on G-CSF 1.20 x 10/l). Treatment increased spleen size (before G-CSF, 47%, on treatment on G-CSF 76%), and splenomegaly was the dose-limiting adverse effect of treatment (pain and early satiety). Clinical observations and records attest to reduce frequency of infectious events and the severity of inflammatory bowel symptoms, but fever and recurrent infections remain a significant problem. In the cohort of patients followed carefully through the Severe Chronic Neutropenia International Registry, four patients have developed myelodysplasia or acute myeloid leukemia and we are aware of four other cases, (altogether seven on G-CSF, one never treated with G-CSF). Liver transplantation in five patients did not correct neutropenia. Four patients had hematopoietic stem cell transplantation; two adults and two children were transplanted; one adult and one child survived. SUMMARY: GSD Ib is a complex disorder of glucose metabolism causing severe chronic neutropenia. G-CSF is effective to raise blood neutrophil counts and reduce fevers and infections in most patients. In conjunction with other therapies (salicylates, mesalamine sulfasalazine and prednisone), G-CSF ameliorates inflammatory bowel symptoms, but doses must be limited because it increases spleen size associated with abdominal pain.

Diagnosis and management of glycogen storage diseases type VI and IX: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).

PURPOSE: Glycogen storage disease (GSD) types VI and IX are rare diseases of variable clinical severity affecting primarily the liver. GSD VI is caused by deficient activity of hepatic glycogen phosphorylase, an enzyme encoded by the PYGL gene. GSD IX is caused by deficient activity of phosphorylase kinase (PhK), the enzyme subunits of which are encoded by various genes: ɑ (PHKA1, PHKA2), ß (PHKB), É£ (PHKG1, PHKG2), and δ (CALM1, CALM2, CALM3). Glycogen storage disease types VI and IX have a wide spectrum of clinical manifestations and often cannot be distinguished from each other, or from other liver GSDs, on clinical presentation alone. Individuals with GSDs VI and IX can present with hepatomegaly with elevated serum transaminases, ketotic hypoglycemia, hyperlipidemia, and poor growth. This guideline for the management of GSDs VI and IX was developed as an educational resource for health-care providers to facilitate prompt and accurate diagnosis and appropriate management of patients. METHODS: A national group of experts in various aspects of GSDs VI and IX met to review the limited evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management. Evidence bases for these rare disorders are largely based on expert opinion, particularly when targeted therapeutics that have to clear the US Food and Drug Administration (FDA) remain unavailable. RESULTS: This management guideline specifically addresses evaluation and diagnosis across multiple organ systems involved in GSDs VI and IX. Conditions to consider in a differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, and prenatal diagnosis are addressed. CONCLUSION: A guideline that will facilitate the accurate diagnosis and optimal management of patients with GSDs VI and IX was developed. This guideline will help health-care providers recognize patients with GSDs VI and IX, expedite diagnosis, and minimize adverse sequelae from delayed diagnosis and inappropriate management. It will also help identify gaps in scientific knowledge that exist today and suggest future studies.

Complex patterns of inheritance, including synergistic heterozygosity, in inborn errors of metabolism: Implications for precision medicine driven diagnosis and treatment.

Inborn errors of metabolism have traditionally been viewed as the quintessential single gene disorders; defects in one gene leads to loss of activity of one enzyme causing a metabolic imbalance and clinical disease. However, reality has never been quite that simple, and the classic "one gene-one enzyme" paradigm has been upended in many ways. Multiple gene defects can lead to the same biochemical phenotype, often with different clinical symptoms. Additionally, different mutations in the same gene can cause variable phenotypes, often most dramatic when a disease can be identified by pre-symptomatic screening. Moreover, response to therapy is not homogeneous across diseases and specific mutations. Perhaps the biggest deviation from traditional monogenic inheritance is in the setting of synergistic heterozygosity, a multigenic inheritance pattern in which mutations in multiple genes in a metabolic pathway lead to sufficient disruption of flux through the pathway, mimicking a monogenic disorder caused by homozygous defects in one gene in that pathway. In addition, widespread adoption of whole exome and whole genome sequencing in medical genetics has led to the realization that individual patients with apparently hybrid phenotypes can have mutations in more than one gene, leading to a mixed genetic disorder. Each of these situations point to a need for as much precision as possible in diagnosing metabolic disease, and it is likely to become increasingly critical to drive therapy. This article examines examples in traditional monogenic disorders that illustrates these points and define inborn errors of metabolism as complex genetic traits on the leading edge of precision medicine.

Safety issues associated with dietary management in patients with hepatic glycogen storage disease.

INTRODUCTION: Hepatic glycogen storage diseases (GSDs) are a group of inherited disorders of carbohydrate metabolism for which dietary management is the cornerstone. Safety and acute complications associated with dietary management have been poorly documented. We hypothesized that safety issues and complications associated with dietary management are prevalent amongst patients with these ultra-rare disorders. METHODS: A questionnaire was developed consisting of 40 questions and was distributed via eight GSD patient organizations from multiple countries. Respondents were (caregivers of) patients with self-reported hepatic GSD. RESULTS: 249 GSD patients from 26 countries responded with a median age of 14.8 years (range: 0.5-66.1). Although management was considered safe by 71% of patients, 51% reported at least one acute complication associated with dietary management, with a total number of 425 reported complications. Most frequently reported causes were: not waking up by an alarm clock (n = 70), forgetting a meal (n = 57) and infections (n = 43). Most frequently reported complications were: hypoglycemia (n = 112), hospital admissions (n = 79) and drowsiness (n = 74). Most complications occurred before the age of 12 years (82%; 637/774 total number of reported events) and during night time (63%; 340/536). Only 61% (152/249) of the GSD patients reported using a written emergency protocol. CONCLUSIONS: Safety issues and complications associated with dietary management are prevalently reported by (caregivers of) 249 GSD patients. A discrepancy has been observed between the patient's perspective on safety of dietary management and occurrence of complications as a result of dietary management.

Long-term safety and efficacy of AAV gene therapy in the canine model of glycogen storage disease type Ia.

BACKGROUND: Viral mediated gene therapy has progressed after overcoming early failures, and gene therapy has now been approved for several conditions in Europe and the USA. Glycogen storage disease (GSD) type Ia, caused by a deficiency of glucose-6-phosphatase-α, has been viewed as an outstanding candidate for gene therapy. This follow-up report describes the long-term outcome for the naturally occurring GSD-Ia dogs treated with rAAV-GPE-hG6PC-mediated gene therapy. METHODS: A total of seven dogs were treated with rAAV-GPE-hG6PC-mediated gene therapy. The first four dogs were treated at birth, and three dogs were treated between 2 and 6 months of age to assess the efficacy and safety in animals with mature livers. Blood and urine samples, radiographic studies, histological evaluation, and biodistribution were assessed. RESULTS: Gene therapy improved survival in the GSD-Ia dogs. With treatment, the biochemical studies normalized for the duration of the study (up to 7 years). None of the rAAV-GPE-hG6PC-treated dogs had focal hepatic lesions or renal abnormalities. Dogs treated at birth required a second dose of rAAV after 2-4 months; gene therapy after hepatic maturation resulted in improved efficacy after a single dose. CONCLUSION: rAAV-GPE-hG6PC treatment in GSD-Ia dogs was found to be safe and efficacious. GSD-Ia is an attractive target for human gene therapy since it is a monogenic disorder with limited tissue involvement. Blood glucose and lactate monitoring can be used to assess effectiveness and as a biomarker of success. GSD-Ia can also serve as a model for other hepatic monogenic disorders.

Tight metabolic control plus ACE inhibitor therapy improves GSD I nephropathy.

The onset of microalbuminuria (MA) heralds the onset of glomerulopathy in patients with glycogen storage disease (GSD) type I. Unlike tubulopathy, which responds to improved metabolic control, glomerulopathy in GSD I is considered refractory to medical intervention, and it is thought to inexorably progress to overt proteinuria and renal failure. Recent reports of reduced microalbuminuria following strict adherence to therapy counter this view. In contrast to type Ia, little is known regarding the prevalence of kidney disease in GSD Ib, 0, III, VI, and IX. Subjects were evaluated with 24-h urine collections between 2005 and 2014 as part of a longitudinal study of the natural history of GSD. ACE inhibitor therapy (AIT) was commenced after documentation of microalbuminuria. Elevated urine albumin excretion was detected in 23 of 195 GSD Ia patients (11.7%) and six of 45 GSD Ib (13.3%). The median age of onset of microalbuminuria in GSD Ia was 24 years (range 9-56); in GSD Ib it was 25 years (range 20-38). Of 14 with GSD Ia who complied with dietary and AIT during the study period, microalbuminuria decreased in 11, in whom metabolic control improved. All 135 patients with the ketotic forms of GSD (0, III, VI and IX) consistently had normal microalbumin excretion. Strict adherence to dietary therapy and maintenance of optimal metabolic control is necessary to halt the progression of GSD Ia glomerulopathy in patients treated with AIT. With optimal care, protein excretion can be reduced and even normalize.

Clinical and biochemical heterogeneity between patients with glycogen storage disease type IA: the added value of CUSUM for metabolic control.

OBJECTIVE: To study heterogeneity between patients with glycogen storage disease type Ia (GSD Ia), a rare inherited disorder of carbohydrate metabolism caused by the deficiency of glucose-6-phosphatase (G6Pase). STUDY DESIGN: Descriptive retrospective study of longitudinal clinical and biochemical data and long-term complications in 20 GSD Ia patients. We included 11 patients with homozygous G6PC mutations and siblings from four families carrying identical G6PC genotypes. To display subtle variations for repeated triglyceride measurements with respect to time for individual patients, CUSUM-analysis graphs were constructed. RESULTS: Patients with different homozygous G6PC mutations showed important differences in height, BMI, and biochemical parameters (i.e., lactate, uric acid, triglyceride, and cholesterol concentrations). Furthermore, CUSUM-analysis predicts and displays subtle changes in longitudinal blood triglyceride concentrations. Siblings in families also displayed important differences in biochemical parameters (i.e., lactate, uric acid, triglycerides, and cholesterol concentrations) and long-term complications (i.e., liver adenomas, nephropathy, and osteopenia/osteoporosis). CONCLUSIONS: Differences between GSD Ia patients reflect large clinical and biochemical heterogeneity. Heterogeneity between GSD Ia patients with homozygous G6PC mutations indicate an important role of the G6PC genotype/mutations. Differences between affected siblings suggest an additional role (genetic and/or environmental) of modifying factors defining the GSD Ia phenotype. CUSUM-analysis can facilitate single-patient monitoring of metabolic control and future application of this method may improve precision medicine for patients both with GSD and remaining inherited metabolic diseases.

Use of Skin Biopsies Among Dermatologists.

BACKGROUND: Skin biopsies are essential to establish a diagnosis in many skin diseases. Utilization has been increasing rapidly and represents a significant health care cost. There are no benchmarks or baselines to guide the practice of skin biopsies. OBJECTIVE: To create a reference data set of biopsy behavior among dermatologists. METHODS: Five hundred eighty-eight dermatologists belonging to the American Dermatological Association (ADA) were surveyed. Two hundred eighty-seven responded with 128 of those providing biopsy data. RESULTS: The mean percentage of biopsies that were malignant was 44.5%. This varied by subspecialty with a mean of 41.7%, 57.4%, and 4.1% of biopsies performed by general dermatologists, Mohs micrographic surgeons, and pediatric dermatologists, respectively. By category or diagnosis, the biopsies were 22.7% basal cell carcinoma, 12.0% SCC, 10.2% benign neoplasms, 10.0% nevi, 8.0% actinic keratosis, 7.6% seborrheic keratosis, 7.5% inflammatory disorders, 6.1% SCC in situ, 5.3% dysplastic nevus, 5.1% benign skin, 1.5% melanoma in situ, 1.4% melanoma, 0.9% lentigines, 0.8% other malignancies, 0.6% infectious, 0.2% not otherwise specified, and 0.1% atypical lesions. There was a statistically significant difference in biopsy results between different dermatological subspecialties. CONCLUSION: These results should help elucidate dermatologic practice patterns and thus create opportunities to improve dermatologic care and reduce health care costs.

Molecular mechanisms of neutrophil dysfunction in glycogen storage disease type Ib.

Glycogen storage disease type Ib (GSD-Ib) is an autosomal-recessive syndrome characterized by neutropenia and impaired glucose homeostasis resulting from a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT). The underlying cause of GSD-Ib neutropenia is an enhanced neutrophil apoptosis, but patients also manifest neutrophil dysfunction of unknown etiology. Previously, we showed G6PT interacts with the enzyme glucose-6-phosphatase-ß (G6Pase-ß) to regulate the availability of G6P/glucose in neutrophils. A deficiency in G6Pase-ß activity in neutrophils impairs both their energy homeostasis and function. We now show that G6PT-deficient neutrophils from GSD-Ib patients are similarly impaired. Their energy impairment is characterized by decreased glucose uptake and reduced levels of intracellular G6P, lactate, adenosine triphosphate, and reduced NAD phosphate, whereas functional impairment is reflected in reduced neutrophil respiratory burst, chemotaxis, and calcium mobilization. We further show that the mechanism of neutrophil dysfunction in GSD-Ib arises from activation of the hypoxia-inducible factor-1α/peroxisome-proliferators-activated receptor-γ pathway.

Glycogen storage disease type III: diagnosis, genotype, management, clinical course and outcome.

Glycogen storage disease type III (GSDIII) is a rare disorder of glycogenolysis due to AGL gene mutations, causing glycogen debranching enzyme deficiency and storage of limited dextrin. Patients with GSDIIIa show involvement of liver and cardiac/skeletal muscle, whereas GSDIIIb patients display only liver symptoms and signs. The International Study on Glycogen Storage Disease (ISGSDIII) is a descriptive retrospective, international, multi-centre cohort study of diagnosis, genotype, management, clinical course and outcome of 175 patients from 147 families (86 % GSDIIIa; 14 % GSDIIIb), with follow-up into adulthood in 91 patients. In total 58 AGL mutations (non-missense mutations were overrepresented and 21 novel mutations were observed) were identified in 76 families. GSDIII patients first presented before the age of 1.5 years, hepatomegaly was the most common presenting clinical sign. Dietary management was very diverse and included frequent meals, uncooked cornstarch and continuous gastric drip feeding. Chronic complications involved the liver (hepatic cirrhosis, adenoma(s), and/or hepatocellular carcinoma in 11 %), heart (cardiac involvement and cardiomyopathy, in 58 % and 15 %, respectively, generally presenting in early childhood), and muscle (pain in 34 %). Type 2 diabetes mellitus was diagnosed in eight out of 91 adult patients (9 %). In adult patients no significant correlation was detected between (non-) missense AGL genotypes and hepatic, cardiac or muscular complications. This study demonstrates heterogeneity in a large cohort of ageing GSDIII patients. An international GSD patient registry is warranted to prospectively define the clinical course, heterogeneity and the effect of different dietary interventions in patients with GSDIII.

In vitro digestion of starches in a dynamic gastrointestinal model: an innovative study to optimize dietary management of patients with hepatic glycogen storage diseases.

Uncooked cornstarch (UCCS) is a widely used treatment strategy for patients with hepatic glycogen storage disease (GSD). It has been observed that GSD-patients display different metabolic responses to different cornstarches. The objective was to characterize starch fractions and analyze the digestion of different starches in a dynamic gastrointestinal in vitro model. The following brands of UCCS were studied: Argo and Great Value from the United States of America; Brazilian Maizena Duryea and Yoki from Brazil; Dutch Maizena Duryea from the Netherlands. Glycosade, a modified starch, and sweet polvilho, a Brazilian starch extracted from cassava, were also studied. The starch fractions were analyzed by glycemic TNO index method and digestion analyses were determined by the TIM-1 system, a dynamic, computer-controlled, in vitro gastrointestinal model, which simulates the stomach and small intestine. The final digested amounts were between 84 and 86% for the UCCS and Glycosade, but was 75.5% for sweet povilho. At 180 min of the experiment, an important time-point for GSD patients, the digested amount of the starches corresponded to 67.9-71.5 for the UCCS and Glycosade, while it was 55.5% for sweet povilho. In an experiment with a mixture of sweet polvilho and Brazilian Maizena Duryea, a final digested amount of 78.4% was found, while the value at 180 min was 61.7%. Sweet polvilho seems to have a slower and extended release of glucose and looks like an interesting product to be further studied as it might lead to extended normoglycemia in GSD-patients.

Evaluation of glycogen storage disease as a cause of ketotic hypoglycemia in children.

INTRODUCTION: Ketone formation is a normal response when hypoglycemia occurs. Since the majority of children with recurrent hypoglycemia cannot be diagnosed with a known endocrine or metabolic disorder on a critical sample, ketotic hypoglycemia has been described as the most common cause of low blood glucose concentrations in children. Critical samples, however, will miss the ketotic forms of glycogen storage disease (GSD), which present with elevated ketones, hypoglycemia, and normal hormonal concentrations. RESULTS: A total of 164 children (96 boys, 68 girls) were enrolled in the study. Prediction of pathogenicity of DNA changes using computer modeling confirmed pathology in 20 individuals [four GSD 0, two GSD VI, 12 GSD IX alpha, one GSD IX beta, one GSD IX gamma] (12%). Boys were most likely to have changes in the PHKA2 gene, consistent with GSD IX alpha, an X-linked disorder. CONCLUSIONS: Mutations in genes involved in glycogen synthesis and degradation were commonly found in children with idiopathic ketotic hypoglycemia. GSD IX is likely an unappreciated cause of ketotic hypoglycemia in children, while GSD 0 and VI are relatively uncommon. GSD IX alpha should particularly be considered in boys with unexplained hypoglycemia.