Renal disease in type I glycogen storage disease

Although kidney enlargement occurs in Type I glycogen storage disease, renal disease has not been considered a major problem. Death from renal failure in three patients known to us prompted a study of renal function in this disorder. Of the 38 patients with Type I glycogen storage disease under our care, the 18 children under 10 years old had normal renal function. Fourteen of the 20 older patients (13 to 47 years) had disturbed renal function, manifested by persistent proteinuria; many also had hypertension, hematuria, or altered creatinine clearance. Progressive renal insufficiency developed in 6 of these 14 patients, leading to three deaths from renal failure. At the onset of proteinuria, creatinine clearance was increased in seven patients (3.05 +/- 0.68 ml per second per 1.73 m2 of body-surface area; range, 2.47 to 4.13 [normal range, 1.33 to 2.33 ml per second per 1.73 m2]). Renal biopsies were performed in three patients after an average of 10 years of proteinuria. All three biopsies demonstrated focal segmental glomerulosclerosis in various stages of progression. Our data suggest that chronic renal disease is a frequent and potentially serious complication of Type I glycogen storage disease. In addition to treating hypoglycemia vigorously, physicians should monitor renal function carefully in patients with this disorder.     

肝糖原累积症-I型的肾脏改变

本文观察了14例临床或病理诊断的肝糖原累积症-Ⅰ型(GSD),年龄3月-19岁,5例(36%)伴有肾脏改变.其中1例,8岁,仅血β_2-M轻度升高,4例大于12岁.4例中2例表现为轻度蛋白尿,3例内生肌酐清除率降低,3例β_2-M轻度升高,1例伴继发性Fanconi综合征和肾性佝倭病表现.1例(14岁)进行了肾活检,光镜下示系膜基质轻度增生,肾小管胞浆内有糖原物质沉积.观察结果表明GSD-Ⅰ型病人的肾脏改变较为普遍,应密切追随肾脏情况,以期经过合理饮食治疗后能延缓本病晚期肾功能恶化.     

Renal glomerular and tubular abnormalities in glycogen storage disease type I

Three children had renal histopathologic findings indicative of glycogen storage disease type I. Glomerular basement membrane (GBM) alterations were present in the three patients, particularly so in the two patients with proteinuria. Thickening, lamellation, and glycogen deposition were the characteristic alterations in the GBM. Glomerulosclerosis was prominent in one patient. We suggest that the GBM alteration is related to the glomerular sclerosis and that both are related to metabolic derangements of glycogen storage disease type I.     

Hemorrhagic pancreatitis in a patient with glycogen storage disease type I

A 17–year-old female with glycogen storage disease type I (GSD-I) died suddenly with hemorrhagic pancreatitis. She had a long-standing history of hyperlipidemia that did not respond to a regimen of frequent daytime and nocturnal intragastric feeding. Although pancreatitis is a well-known complication of hyperlipidemia, there are no reports to our knowledge of pancreatitis causing sudden death in patients with GSD-I. Pancreatitis must be added to the growing list of complications that can occur in long-term survivors with GSD-I, and should be considered when these patients present with abdominal pain.     

Molecular diagnosis of glycogen storage disease type IX using a glycogen storage disease gene panel

Glycogen storage disease type IX (GSD IX) is caused by a deficiency of hepatic phosphorylase kinase. The aim of this study was to clarify the clinical features, long term outcomes, and genetic analysis of GSD IX in Korea. A GSD gene panel was created and hybridization capture-based next-generation sequencing was performed. We investigated clinical laboratory data, results of molecular genetic analysis, liver biopsy findings, and long-term outcomes. Ten children were diagnosed with GSD IX at Seoul National University Children's Hospital. Hypoglycemia, hyperlactacidemia, hypertriglyceridemia, hyperuricemia, liver fibrosis on liver biopsy, and short stature was found in 30%, 56%, 100%, 60%, 80% and 50% of the children, respectively. Seven PHKA2 variants were identified in eight children with GSD IXa—one nonsense (c.2268dupT; p.(Asp757Ter)), two splicing (c.918+1G > A, c.718-2A > G), one frameshift (c.405_419delinsTCCTGGCC; p.(Asp136ProfsTer11)), and three missense variants (c.3628G > A; p.(Gly1210Arg), c.1245G > T and c.2746C > T; p.(Arg916Trp)). Two variants of PHKG2 were identified in two children with GSD IXc—one frameshift (c.783delC; p.(Ser262AlafsTer6)) and one missense (c.661G > A; p.(Val221Met)). Elevated liver enzymes and hypertriglyceridemia in children with GSD IXa tended to improve with age. For the first time, we report hepatocellular carcinoma in a patient with GSD IXc. The GSD gene panel is a useful diagnostic tool to confirm GSD IX. The clinical phenotype of GSD IXc is severe and monitoring for the development of hepatocellular carcinoma should be implemented.     

Non-lethal congenital hypotonia due to glycogen storage disease type IV

Glycogen storage disease type IV (GSD-IV) is an autosomal recessive genetic disorder due to a deficiency in the activity of the glycogen branching enzyme (GBE). A deficiency in GBE activity results in the accumulation of glycogen with fewer branching points and long, unbranched outer chains. The disorder results in a variable phenotype, including musculoskeletal, cardiac, neurological, and hepatic involvement, alone or in continuum, which can be identified at any stage of life. The classic form of GSD-IV is a hepatic presentation, which presents in the first 18 months of life with failure to thrive, hepatomegaly, and cirrhosis that progresses to liver failure, resulting in death by age 5 years. A severe congenital musculoskeletal phenotype with death in the neonatal period has also been described. We report an unusual case of congenital musculoskeletal presentation of GSD-IV with stable congenital hypotonia, gross motor delay, and severe fibro-fatty replacement of the musculature, but no hepatic or cardiac involvement. Molecular analysis revealed two novel missense mutations with amino acid changes in the GBE gene (Q236H and R262C), which may account for the mild phenotype.     

Gene therapy for type I glycogen storage diseases

The type I glycogen storage diseases (GSD-I) are a group of related diseases caused by a deficiency in the glucose-6-phosphatase-alpha (G6Pase-alpha) system, a key enzyme complex that is essential for the maintenance of blood glucose homeostasis between meals. The complex consists of a glucose-6-phosphate transporter (G6PT) that translocates glucose-6-phosphate from the cytoplasm into the lumen of the endoplasmic reticulum, and a G6Pase-alpha catalytic unit that hydrolyses the glucose-6-phosphate into glucose and phosphate. A deficiency in G6Pase-alpha causes GSD type Ia (GSD-Ia) and a deficiency in G6PT causes GSD type Ib (GSD-Ib). Both GSD-Ia and GSD-Ib patients manifest a disturbed glucose homeostasis, while GSD-Ib patients also suffer symptoms of neutropenia and myeloid dysfunctions. G6Pase-alpha and G6PT are both hydrophobic endoplasmic reticulum-associated transmembrane proteins that can not expressed in soluble active forms. Therefore protein replacement therapy of GSD-I is not an option. Animal models of GSD-Ia and GSD-Ib that mimic the human disorders are available. Both adenovirus- and adeno-associated virus (AAV)-mediated gene therapies have been evaluated for GSD-Ia in these model systems. While adenoviral therapy produces only short term corrections and only impacts liver expression of the gene, AAV-mediated therapy delivers the transgene to both the liver and kidney, achieving longer term correction of the GSD-Ia disorder, although there are substantial differences in efficacy depending on the AAV serotype used. Gene therapy for GSD-Ib in the animal model is still in its infancy, although an adenoviral construct has improved the metabolic profile and myeloid function. Taken together further refinements in gene therapy may hold long term benefits for the treatment of type I GSD disorders.     

Molecular genetics of type 1 glycogen storage disease

Glycogen storage disease type 1 (GSD 1) comprises a group of autosomal recessive inherited metabolic disorders caused by deficiency of the microsomal multicomponent glucose-6-phosphatase system. Of the two known transmembrane proteins of the system, malfunction of the catalytic subunit (G6Pase) characterizes GSD 1a. GSD 1 non-a is characterized by defective microsomal glucose-6-phosphate or pyrophosphate/phosphate transport due to mutations in G6PT (glucose-6-phosphate translocase gene) encoding a microsomal transporter protein. Mutations in G6Pase and G6PT account for approximately 80 and approximately 20% of GSD 1 cases, respectively. G6Pase and G6PT work in concert to maintain glucose homeostasis in gluconeogenic organs. Whereas G6Pase is exclusively expressed in gluconeogenic cells, G6PT is ubiquitously expressed and its deficiency generally causes a more severe phenotype. Rapid confirmation of clinically suspected diagnosis of GSD 1, reliable carrier testing, and prenatal diagnosis are facilitated by mutation analyses of the chromosome 11-bound G6PT gene as well as the chromosome 17-bound G6Pase gene.     

Mouse model of glycogen storage disease type III

Glycogen storage disease type IIIa (GSD IIIa) is caused by a deficiency of the glycogen debranching enzyme (GDE), which is encoded by the Agl gene. GDE deficiency leads to the pathogenic accumulation of phosphorylase limit dextrin (PLD), an abnormal glycogen, in the liver, heart, and skeletal muscle. To further investigate the pathological mechanisms behind this disease and develop novel therapies to treat this disease, we generated a GDE-deficient mouse model by removing exons after exon 5 in the Agl gene. GDE reduction was confirmed by western blot and enzymatic activity assay. Histology revealed massive glycogen accumulation in the liver, muscle, and heart of the homozygous affected mice. Interestingly, we did not find any differences in the general appearance, growth rate, and life span between the wild-type, heterozygous, and homozygous affected mice with ad libitum feeding, except reduced motor activity after 50 weeks of age, and muscle weakness in both the forelimb and hind legs of homozygous affected mice by using the grip strength test at 62 weeks of age. However, repeated fasting resulted in decreased survival of the knockout mice. Hepatomegaly and progressive liver fibrosis were also found in the homozygous affected mice. Blood chemistry revealed that alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) activities were significantly higher in the homozygous affected mice than in both wild-type and heterozygous mice and the activity of these enzymes further increased with fasting. Creatine phosphokinase (CPK) activity was normal in young and adult homozygous affected mice. However, the activity was significantly elevated after fasting. Hypoglycemia appeared only at a young age (3 weeks) and hyperlipidemia was not observed in our model. In conclusion, with the exception of normal lipidemia, these mice recapitulate human GSD IIIa; moreover, we found that repeated fasting was detrimental to these mice. This mouse model will be useful for future investigation regarding the pathophysiology and treatment strategy of human GSD III.     

Hepatic adenomata in type Ia glycogen storage disease

Liver adenomata are common in young adults and adults with type Ia glycogen storage disease. Complications that may arise in these patients include acute hemorrhage and malignant transformation. With appropriate dietary therapy, they may partially or completely regress. We describe a young woman with type Ia glycogenosis who developed liver adenomata. Because of its persistence and the significant potential of malignant transformation, liver transplantation was performed. This case is discussed in light of a review of the literature on the subject.     

Optimal rate of enteral glucose administration in children with glycogen storage disease type I

Rates of administration of enteral carbohydrate to maintain the plasma glucose concentration and suppress organic acidemia in young children with glycogen storage disease Type I have not been clearly established. Therefore, we studied six children with the disease during sequential nasogastric infusions of carbohydrate at four different rates (10.5, 8.6, 5.8, and 3 mg of carbohydrate per kilogram of body weight per minute). The rates at which total and endogenous glucose appeared in the plasma were measured with [2H2] glucose. The infusion rates of carbohydrate were linearly correlated (r = 0.88, P less than 0.001) with the plasma glucose concentration, which was about 90 mg per deciliter at a rate of 8.6 mg per kilogram per minute. The mean (+/- SE) rate of appearance of endogenous glucose was 1.4 +/- 0.1 mg per kilogram per minute at a nasogastric infusion rate of 5.8 mg of carbohydrate per kilogram per minute (a rate similar to that of hepatic glucose production in normal children who have fasted overnight), and was completely suppressed at 10.5 mg of carbohydrate per kilogram per minute. Concentrations of plasma lactate, pyruvate, free fatty acids, and ketone bodies were inversely related to the rate of carbohydrate administration below 8.6 mg per kilogram per minute. We conclude that the minimal nocturnal nasogastric infusion rate of carbohydrate needed to maintain plasma glucose concentrations and minimize organic acidemia in young children with glycogen storage disease Type I is approximately 8 to 9 mg per kilogram per minute.     

Glycemic control and complications in glycogen storage disease type I: Results from the Swiss registry

BackgroundRegular carbohydrate intake to avoid hypoglycemia is the mainstay of dietary treatment in glycogen storage disease type I (GSDI). The aim of this study was to evaluate the quality of dietary treatment and glycemic control in a cohort of GSDI patients, in relation to the presence of typical long-term complications.MethodsData of 25 patients (22 GSD subtype Ia and 3 GSDIb, median age 20y) from the Swiss hepatic glycogen storage disease registry was analyzed cross-sectionally. Frequency and type of hypoglycemia symptoms were assessed prospectively using a structured questionnaire. Diagnostic continuous glucose monitoring (CGM) was performed as part of usual clinical care to assess glycemic control in 14 patients, usually once per year with a mean duration of 6.2 ± 1.1 consecutive days per patient per measurement.ResultsAlthough maintenance of euglycemia is the primary goal of dietary treatment, few patients (n = 3, 13%) performed capillary blood glucose measurements regularly. Symptoms possibly associated with hypoglycemia were present in 13 patients (57%), but CGM revealed periods of low glucose (<4 mmol/l) in all patients, irrespective of the presence of symptoms. GSDIa patients with liver adenomas (n = 9, 41%) showed a higher frequency and area under the curve (AUC) of low blood glucose than patients without adenomas (frequency 2.7 ± 0.8 vs. 1.5 ± 0.7 per day, AUC 0.11 ± 0.08 vs. 0.03 ± 0.02 mmol/l/d; p < 0.05). Similarly, the presence of microalbuminuria was also associated with the frequency of low blood glucose. Z-Scores of bone density correlated negatively with lactate levels.ConclusionThe quality of glucose control is related to the presence of typical long-term complications in GSDI. Many patients experience episodes of asymptomatic low blood glucose. Regular assessment of glucose control is an essential element to evaluate the quality of treatment, and increasing the frequency of glucose self-monitoring remains an important goal of patient education and motivation. CGM devices may support patients to optimize dietary therapy in everyday life.     

Identification of a mutation in liver glycogen phosphorylase in glycogen storage disease type VI

Glycogen storage disease type VI (GSD6) defines a group of disorders that cause hepatomegaly and hypoglycemia with reduced liver phosphorylase activity. The course of these disorders is generally mild, but definitive diagnosis requires invasive procedures. We analyzed a Mennonite kindred with an autosomal recessive form of GSD6 to determine the molecular defect and develop a non-invasive diagnostic test. Linkage analysis was performed using genetic markers flanking the liver glycogen phosphorylase gene ( PYGL ), which was suspected to be the cause of the disorder on biochemical grounds. Mennonite GSD6 was linked to the PYGL locus with a multipoint LOD score of 4.7. The PYGL gene was analyzed for mutations by sequencing genomic DNA. Sequencing of genomic DNA revealed a splice site abnormality of the intron 13 splice donor. Confirmation of the genomic mutation was performed by sequencing RT-PCR products, which showed heterogeneous PYGL mRNA lacking all or part of exon 13 in affected persons. This study is the first to demonstrate that a mutation in the PYGL gene can cause GSD6. This mutation is estimated to be present on 3% of Mennonite chromosomes and the disease affects 0.1% of that population. Determination of this mutation provides a basis for the development of a simple and non- invasive diagnostic test for the disease and the carrier state in this population and confirms biochemical data showing the importance of this gene in glucose homeostasis.      

Noncompaction myocardium in association with type Ib glycogen storage disease

Noncompaction myocardium is a rare disorder assumed to occur as an arrest of the compaction process during the normal development of the heart. Left ventricular noncompaction has been reported to be associated with a variety of cardiac and extracardiac, especially neuromuscular abnormalities. Moreover, it has been suggested that metabolic alterations could be responsible for the noncompaction. However, no association of noncompaction myocardium with type Ib glycogen storage disease (GSD) has been reported so far. Type Ib GSD is due to a defect of a transmembrane protein which results, similar to type Ia GSD, in hypoglycemia, a markedly enlarged liver and, additionally, in neutropenia, recurrent infections, and inflammatory bowel disease. Until now, no muscular or cardiac involvement has been described in type Ib GSD patients. The present case represents the first report of a noncompaction myocardium in a child with type Ib GSD who died of sudden clinical deterioration at the age of four.     

Activation of glycolysis and apoptosis in glycogen storage disease type Ia

The deficiency of glucose-6-phosphatase (G6Pase) underlies glycogen storage disease type Ia (GSD-Ia, von Gierke disease; MIM 232200), an autosomal recessive disorder of metabolism associated with life-threatening hypoglycemia, growth retardation, renal failure, hepatic adenomas, and hepatocellular carcinoma. Liver involvement includes the massive accumulation of glycogen and lipids due to accumulated glucose-6-phosphate and glycolytic intermediates. Proteomic analysis revealed elevations in glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and other enzymes involved in glycolysis. GAPDH was markedly increased in murine G6Pase-deficient hepatocytes. The moonlighting role of GAPDH includes increasing apoptosis, which was demonstrated by increased TUNEL assay positivity and caspase 3 activation in the murine GSD-Ia liver. These analyses of hepatic involvement in GSD-Ia mice have implicated the induction of apoptosis in the pathobiology of GSD-Ia.     

Molecular characterization of Egyptian patients with glycogen storage disease type IIIa

Glycogen storage disease type IIIa (GSD IIIa) is an autosomal recessive disorder characterized by excessive accumulation of abnormal glycogen in the liver and muscles and caused by a deficiency in the glycogen debranching enzyme. The spectrum of AGL mutations in GSD IIIa patients depends on ethnic group—prevalent mutations have been reported in the North African Jewish population and in an isolate such as the Faroe islands, because of the founder effect, whereas heterogeneous mutations are responsible for the pathogenesis in Japanese patients. To shed light on molecular characteristics in Egypt, where high rate of consanguinity and large family size increase the frequency of recessive genetic diseases, we have examined three unrelated patients from the same area in Egypt. We identified three different individual AGL mutations; of these, two are novel deletions [4-bp deletion (750–753delAGAC) and 1-bp deletion (2673delT)] and one the nonsense mutation (W1327X) previously reported. All are predicted to lead to premature termination, which completely abolishes enzyme activity. Three consanguineous patients are homozygotes for their individual mutations. Haplotype analysis of mutant AGL alleles showed that each mutation was located on a different haplotype. Our results indicate the allelic heterogeneity of the AGL mutation in Egypt. This is the first report of AGL mutations in the Egyptian population.     

晚发型糖原贮积病Ⅱ型一例

患儿男,15岁,因"体重不增、运动能力倒退5年"就诊。患儿于1岁多会走,跑步易跌倒,语言、智力发育正常,10岁后出现运动倒退,四肢无力,上下楼梯困难,起蹲费力,走路姿势异常,6岁时有"肾积水"病史,现已痊愈。目前可独站、独行,肌电图显示:肌源性损害,并见肌强直电位。体格检查:消瘦体型,四肢肌力Ⅳ级,肌张力Ⅰ级,余无阳性表现。患儿妹妹10岁,有类似情况,3年前出现消瘦明显,跑步易跌倒,运动较同龄人差,近半年发现走路姿势异常,双脚外八字,肌电图显示:肌源性损害,并见肌强直电位。父母正常,无类似表现。患儿实验室检查:天门冬氨酸转移酶139 U/L(正常参考值13~40 U/L),肌酸激酶747 U/L(正常参考值30~225 U/L),肌酸激酶同工酶53 U/L(正常参考值0~29 U/L),乳酸脱氢酶485 U/L(正常参考值120~330 U/L),羟丁酸脱氢酶381 U/L(正常参考值72~182 U/L);患儿妹妹实验室检查:天门冬氨酸转移酶187 U/L,肌酸激酶1281 U/L,肌酸激酶同工酶45 U/L,乳酸脱氢酶658 U/L,羟丁酸脱氢酶546 U/L。患儿及患儿妹妹血常规、肝肾功能、血脂、血糖、心电图、血乳酸、彩色多普勒超声心动图结果均正常,未监测肺功能。患儿首发症状为肌肉运动障碍,首先考虑为肌肉代谢性疾病,建议患儿及患儿妹妹、父母行基因检测。