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.     

Hepatocellular adenoma and metabolic balance in patients with type Ia glycogen storage disease

Glycogen storage disease type I (GSD I) is a metabolic disorder resulting from defects in the glucose-6-phosphatase system. Approximately 75% of adolescent and adult patients develop hepatocellular adenomas, which can lead to considerable morbidity and mortality. The pathogenesis of adenomas is unclear and the risk of developing adenomas in treated patients is uncertain. The objective of this study was to determine whether metabolic imbalance was related to the occurrence of adenomas in patients with GSD I, and to determine what specific biochemical pathways were involved. We performed a 1:1 case–control retrospective study; cases were GSD I patients with adenomas and controls were GSD I patients without adenomas. Controls and cases were matched according to age at diagnosis, age at adenoma detection, and gender. We investigated biochemical abnormalities indicative of metabolic balance and exogenous factors potentially related to the onset of adenomas in the two groups. We detected no significant differences in dietetic treatment, compliance to treatment, or biochemical parameters related to metabolic balance between the two groups. In conclusion, we were unable to identify any significant differences in metabolic balance between GSD I patients who developed adenomas and those who did not.     

Impact of genotype on neutropenia in a large cohort of Serbian patients with glycogen storage disease type Ib

BackgroundGlycogen storage disease type Ib (GSD-Ib) is an inherited metabolic disorder caused by autosomal recessive mutations in SLC37A4 coding for the glucose-6-phosphate transporter. Neutropenia represents major feature of GSD-Ib along with metabolic disturbances. Previous research in GSD-Ib patients did not reveal significant genotype-phenotype correlation. Our objective was to explore the frequency and severity of neutropenia and it's complications in relation to genotype of GSD-Ib patients.MethodsWe estimated cumulative incidence of neutropenia and severe neutropenia, relation of genotype to absolute neutrophil count (ANC), and dynamics of ANC during serious bacterial infections (SBI) in a cohort of Serbian GSD Ib patients. Impact of genotype on GSD Ib-related inflammatory bowel disease (IBD) was also assessed.ResultsAbsolute neutrophil count (ANC) < 1500/mm³ was present in all 33 patients, with severe neutropenia (ANC<500/mm³) occurring in 60.6% of patients. The median age at neutropenia onset was 24 months, while severe neutropenia developed at median of 4.5 years. The ANC was elevated during 90.5% episodes of SBI. Genotypes c.81T>A/c.785G>A and c.81T>A/c.1042_1043delCT are associated with earlier onset of neutropenia. Patients carrying c.785G>A mutation express a higher capacity for ANC increase during SBI. Inflammatory bowel disease was diagnosed in 8 patients (24.2% of total) with median age of onset at 7 years. Risk for IBD occurrence was not significantly affected by gender, genotype and severity of neutropenia.ConclusionsWe may conclude that certain mutations in SLC37A4 influence the risk for severe neutropenia occurrence but also affect the capacity to increase ANC during SBI.     

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.     

Glucose-6-phosphatase gene mutations in Taiwan Chinese patients with glycogen storage disease type Ia

Glycogen storage disease type Ia (GSD Ia) is caused by a deficiency of glucose-6-phosphatase (G6Pase) activity. Eighteen GSD Ia families were studied for G6Pase gene mutations. Thirty-two mutations were found in 36 GSD Ia chromosomes: 16 were 727 G→T (44.44%); 13 were R83H (327 G→T; 36.11%); 1 was 341delG; 1 was 933insAA; and 1 was 793 G→T. The 727 G→T and R83H mutations together accounted for 80.56% (29/36) of the GSD Ia chromosomes. These two mutations were easily examined by polymerase chain reaction-based methods, and the prenatal diagnosis of a non-affected fetus was successfully made. The 727 G→T mutation is the predominant mutation in Japanese GSD Ia patients, but is rarely seen in Western counties. The 727 G→T mutation is also the most prevalent mutation in Taiwan Chinese, although the incidence is not as high as in Japan. Received: January 4, 2000 / Accepted: February 28, 2000     

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.     

生玉米淀粉治疗肝糖原累积病的临床观察

生玉米淀粉悬液治疗肝糖累积症３例均取得满足疗效，用法是每次１．７５ｇ／ｋｇ，分次口服，其结果表明：服生玉米淀粉后低血糖症状很快控制，空腹血糖治疗前后治疗后相比较平均增加２．０ｍｍｏｌ／Ｌ，肝脏缩小，半年－一年后随访，肝脏平均缩小１－３ｃｍ，身高增加，半年内平均增加３－５ｃｍ，提示生玉米淀粉治疗本病有特殊的疗效，并应特别强调的治疗越早，效果越好，并要坚持长期服用。     

居家护理对慢性阻塞性肺部疾病患者生活质量的影响

目的:探讨居家护理对慢性阻塞性肺部疾病(COPD)患者生活质量的影响。方法:将86例(COPD)患者按出院奇偶数分为观察组和对照组各43例,对照组出院后采用常规护理方法,观察组在此基础上采用居家护理方法,对其生活方式进行干预,采用COPD患者生活质量评定量表,评价两组患者的生活质量,结果:干预6个月后,两组日常生活、社会活动、抑郁、焦虑及生活质量总均分比较,差异有显著性意义(均P<0.05)。结论:居家护理能提高COPD患者的生活质量。     

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.     

帕金森患者的睡眠障碍

目的：探讨帕金森病患者睡眠结构紊乱与病程的长短、病情的严重程度以及用药种类的关系。方法：应用多项睡眠图描记分析技术（polysomnography），分析17例帕金森病患者的睡眠总时间、睡眠效率、睡眠潜伏期、睡眠醒觉的次数和时间。结果：睡眠效率低于80％的15例，睡眠潜伏期大于30min者9例．睡眠中醒觉的时间大于60min者15例。病程大于5年的患者的平均睡眠总时间（173min）与病程小于5年者（276min）相比显著减少，差异具有显著意义（P=0．02）。病程大于5年的患者睡眠潜伏期（72min）较病程小f5年者的睡眠潜伏期（35rain）明显延长，呈明显的正相关（r=0．44，P〈0．05）。H—Y分级与总睡眠时间呈负相关（r=0．49，P〈0．05），与睡眠潜伏期呈正相关（r=0．56，P〈0．05）。服用两种以I：药物哲的睡眠潜伏期较用一种药物者的明显延长（P=0．02）。结论：帕金森病患者的睡眠结构存在明显异常，主要表现为睡眠总时间减少、睡眠效率减低、睡眠觉醒的时间和次数增多及睡眠潜伏期延氐。帕金森病患者病程的长短与总睡眠时间成反比，病情的严重程度与睡眠时间及效率成反比，而与睡眠潜伏期及睡眠中醒觉的次数成正比，用药种类的多少与睡眠潜伏期成正比。     

Glycogen storage disease: long-term follow-up of nocturnal intragastric feeding

Nocturnal intragastric feeding of patients with certain hepatic forms of glycogen storage disease has been advocated as an effective treatment, resulting in improved blood chemical values and linear growth. We are reporting the long-term follow-up of five patients with glycogen storage disease; three with type Ia, one with type Ib, and one with type III disease. All had improvement in one or more of the following: linear growth, serum glutamic oxaloacetate transaminase, total lipids, cholesterol, phospholipids, or triglycerides. None had significant improvement in venous CO₂, serum lactate or urate. One of the patients in this study died after 1.1 years of treatment, and another patient developed hepatocellular carcinoma after 4.4 years of treatment. Nocturnal intragastric feeding, in conjunction with appropriate daytime feeding, is helpful in the management of patients with glycogen storage disease but response to treatment is variable, and it remains to be determined whether the ultimate prognosis of the diseases can be improved.     

Diffuse reticuloendothelial system involvement in type IV glycogen storage disease with a novel GBE1 mutation: a case report and review

Glycogen storage disease type IV is a rare autosomal recessive disorder of glycogen metabolism caused by mutations in the GBE1 gene that encodes the 1,4-alpha-glucan-branching enzyme 1. Its clinical presentation is variable, with the most common form presenting in early childhood with primary hepatic involvement. Histologic manifestations in glycogen storage disease type IV typically consist of intracytoplasmic non-membrane-bound inclusions containing abnormally branched glycogen (polyglucosan bodies) within hepatocytes and myocytes. We report a female infant with classic hepatic form of glycogen storage disease type IV who demonstrated diffuse reticuloendothelial system involvement with the spleen, bone marrow, and lymph nodes infiltrated by foamy histiocytes with intracytoplasmic polyglucosan deposits. Sequence analysis of the GBE1 gene revealed compound heterozygosity for a previously described frameshift mutation (c.1239delT) and a novel missense mutation (c.1279G>A) that is predicted to alter a conserved glycine residue. GBE enzyme analysis revealed no detectable activity. A review of the literature for glycogen storage disease type IV patients with characterized molecular defects and deficient enzyme activity reveals most GBE1 mutations to be missense mutations clustering in the catalytic enzyme domain. Individuals with the classic hepatic form of glycogen storage disease type IV tend to be compound heterozygotes for null and missense mutations. Although the extensive reticuloendothelial system involvement that was observed in our patient is not typical of glycogen storage disease type IV, it may be associated with severe enzymatic deficiency and a poor outcome.     

组织化学和免疫组织化学技术对脂质沉积性肌病和糖原沉积性肌病的鉴别

目的脂质沉积性肌病和糖原沉积性肌病是罕见的肌肉疾病,其常规病理形态十分相似。本文探讨这两种疾病组织化学和免疫组化反应,寻找其鉴别诊断的形态差异。方法采用三磷酸腺苷(ATP)酶、还原性尼克酰胺腺嘌呤二核苷酸(NADH-Tr)、苏丹Ⅲ、PAS组织化学染色和抗肌萎缩蛋白(Dystrophin)免疫组化染色,分析2例脂质沉积性肌病和2例糖原沉积性肌病的组织形态特征和差别。结果脂质沉积性肌病和糖原沉积性肌病在常规HE染色均表现为肌纤维内出现大量的空泡,但前者空泡大小较一致,且边界清楚,后者空泡大小差异大,边界不清。ATP酶组化染色显示脂质沉积性肌病出现空泡变性的肌纤维均为Ⅰ型肌纤维,而糖原沉积性肌病出现空泡变性的肌纤维两型均有,以Ⅰ型严重。脂肪染色和糖原染色可作为这两种肌病的确诊依据。Dystrophin免疫组化染色显示脂质沉积性肌病的肌纤维强阳性,而在糖原沉积性肌病的反应为不连续弱阳性。结论组化和免疫组化检测可用于脂质沉积性肌病和糖原沉积性肌病的鉴别诊断。     

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.     

主诉失眠的门诊就诊者主客观评估的睡眠质量与生命质量

目的:失眠者的主观睡眠感与实际睡眠情况常有不一致的现象,本研究通过探讨以失眠为主诉的门诊就诊者睡眠质量的主观、客观评估指标与生命质量的相关性,为临床制定失眠的整体治疗方案提供参考依据。方法:连续收集64例以失眠为主诉的接受多导睡眠图(PSG)检查的门诊患者的资料,用匹兹堡睡眠质量指数(PSQI)评估主观睡眠质量,SF-36健康调查量表评估生命质量,用贝克抑郁问卷(BDI)、贝克焦虑问卷(BAI)评估情绪状态。以17例正常人的PSG数据作为客观睡眠质量的基础对照。结果:本组失眠就诊者90%主观评价睡眠质量差,其PSG指标中与正常对照相比睡眠潜伏期延长、清醒次数增加、睡眠效率降低、快动眼睡眠潜伏期延长(均P<0.05)。失眠就诊者PSQI总分与SF-36生理健康总分呈负相关(r=-0.25,P<0.05),但以BDI、BAI分作为控制变量进行偏相关分析显示,PSQI总分及各因子分与SF-36生理健康和心理健康总分相关性无统计学意义;PSG主要指标与SF-36生理健康和心理健康总分相关性无统计学意义。结论:本研究显示失眠者主观感受的睡眠质量更可能与生命质量相关,但与失眠相关的抑郁、焦虑情绪可能起到主要作用,这提示失眠治疗中应重视改善患者的主观睡眠质量,以及识别和处理情绪问题。     

Mutational and haplotype analysis of <Emphasis Type="Italic">AGL</Emphasis> in patients with glycogen storage disease type III

Glycogen storage disease type III (GSD III) is a rare autosomal recessive inherited disorder caused by a deficiency of the glycogen-debranching enzyme (AGL). We investigated two GSD III patients and identified four different mutations. Nucleotide sequence analysis revealed patient 1 of Chinese descent to be a compound heterozygote for a novel nonsense mutation, R34X, and the splicing mutation (IVS32−12A > G) reported in a Japanese patient. Patient 2 of Japanese origin was found to be compound heterozygous for a novel nonsense mutation, Y1148X, and the splicing mutation (IVS14+1G > T) that we had described previously. To determine whether splicing mutations occurred independently, we performed intense AGL haplotype analysis using 21 intragenic polymorphic markers plus a novel polymorphism IVS32−97 A/G in the vicinity of the IVS32 splicing mutation. Patient 1 of Chinese origin and the Japanese patient homozygous for the IVS32−12A > G were found to have different haplotypes, indicating the IVS32−12A > G mutation to be a recurrent mutation. This is the first recurrent mutation established by intense haplotyping in the AGL gene. Received: October 3, 2001 / Accepted: November 12, 2001     

Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire

PurposeThis paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib).MethodsThis is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe.ResultsClinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction–related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals.ConclusionEmpagliflozin has a favorable effect on neutropenia/neutrophil dysfunction–related symptoms and safety profile in individuals with GSD Ib.     

阿立哌唑与氟哌啶醇对精神分裂症患者生存质量影响的比较研究

目的 比较阿立哌唑与氟哌啶醇对精神分裂症患者生存质量的影响。方法 将符合条件的80例精神分裂症患者随机分为阿立哌唑组和氟哌啶醇组，治疗3个月，采用阳性与阴性症状量表（PANSS），副反应量表（TESS），健康状况问卷（SF-36）进行疗效、副反应和生存质量评估，并对影响生存质量的某些因素进行多元逐步回归分析。结果 n两组PANSS评分治疗前后差异均有呈著性（P〈0．01），而两组同期相比差异无显著性。治疗结束后，阿立哌唑组在生理机能、生理职能、生活活力、社会功能、情感职能5个因子分及生存质量总评分均明显高于氟哌啶醇组（P〈0．05），且治疗前后评分差异显著。多因素逐步回归分析呈示影响患者生存质量的主要因素依次为精神症状、药物、副反应、病程。结论 阿立哌唑与氟哌啶醇对精神分裂症疗效相当，生存质量影响阿立派唑优于氟哌啶醇。     

以健康测量量表评价癫癎及哮喘患儿生活质量的对照研究

目的以健康测量量表（SF-36）评估癫癎及哮喘患儿的生活质量。方法采用SF-36量表对2007年6至12月在复旦大学附属儿科医院神经专科、呼吸专科及儿童保健门诊就诊的癫癎患儿、哮喘患儿和健康儿童进行生活质量评定。结果研究期间85例癫癎患儿（癫癎组）、81例哮喘患儿（哮喘组）和87名健康儿童（正常对照组）进入分析。3组儿童的年龄、性别和受教育程度相匹配。①疾病及治疗情况：癫癎组和哮喘组服用1种药物者分别为70／85例和59／81例,癫癎组63／85例和哮喘组56／81例患病后规则服药,两组在服药种类和依从性上差异无统计学意义（P均〉0．05）;癫癎组36／85例至本次调查前至少有1年癫癎未发作;哮喘组29／81例最大呼气峰流速监测持续保持个人最佳值的80％以上。②生活质量评价：癫癎组的生活质量总分和8个分项的终得分与正常对照组差异均有统计学意义（P〈0．01）;哮喘组的生活质量总分及生理功能、身体疼痛、总体健康和活力4个分项的终得分与正常对照组差异均有统计学意义（P〈0．01）;无论疾病控制与否,癫癎组生活质量均较哮喘组差;癫癎组情感功能及精神健康状况明显差于哮喘组,其心理障碍不随疾病控制而明显改善。结论①癫癎和哮喘患儿生活质量较健康儿童明显下降;②癫癎患儿较哮喘患儿生活质量损害更为明显;③SF-36量表可作为评价疾病控制程度的手段,辅助评价疾病治疗的疗效;④癫癎患儿的心理障碍应引起临床高度关注。     

Functional analysis of mutations in the glucose-6-phosphate transporter that cause glycogen storage disease type Ib

The glucose-6-phosphate transporter (G6PT) deficient in glycogen storage disease type Ib is a phosphate (P_i)-linked antiporter capable of G6P: P_i and P_i:P_i exchanges. We previously characterized G6PT mutations by measuring G6P uptake activities in microsomes co-expressing G6PT and glucose-6-phosphatase-α. Here we report a new assay, based on reconstituted proteoliposomes carrying only G6PT, and characterize G6P and P_i uptake activities of 23 G6PT mutations. We show that co-expression and G6PT-only assays are equivalent in measuring G6PT activity. However, the p.Q133P mutation exhibits differential G6P and P_i transport activities, suggesting that characterizing G6P and P_i transport activities of G6PT mutations may yield insights to this genetic disorder.