Glycogen storage diseases:An update

Glycogen storage diseases(GSDs),also referred to as glycogenoses,are inherited metabolic disorders of glycogen metabolism caused by deficiency of enzymes or transporters involved in the synthesis or degradation of glycogen leading to aberrant storage and/or utilization.The overall estimated GSD incidence is 1 case per 20000-43000 live births.There are over 20 types of GSD including the subtypes.This heterogeneous group of rare diseases represents inborn errors of carbohydrate metabolism and are classified based on the deficient enzyme and affected tissues.GSDs primarily affect liver or muscle or both as glycogen is particularly abundant in these tissues.However,besides liver and skeletal muscle,depending on the affected enzyme and its expression in various tissues,multiorgan involvement including heart,kidney and/or brain may be seen.Although GSDs share similar clinical features to some extent,there is a wide spectrum of clinical phenotypes.Currently,the goal of treatment is to maintain glucose homeostasis by dietary management and the use of uncooked cornstarch.In addition to nutritional interventions,pharmacological treatment,physical and supportive therapies,enzyme replacement therapy(ERT)and organ transplantation are other treatment approaches for both disease manifestations and longterm complications.The lack of a specific therapy for GSDs has prompted efforts to develop new treatment strategies like gene therapy.Since early diagnosis and aggressive treatment are related to better prognosis,physicians should be aware of these conditions and include GSDs in the differential diagnosis of patients with relevant manifestations including fasting hypoglycemia,hepatomegaly,hypertransaminasemia,hyperlipidemia,exercise intolerance,muscle cramps/pain,rhabdomyolysis,and muscle weakness.Here,we aim to provide a comprehensive review of GSDs.This review provides general characteristics of all types of GSDs with a focus on those with liver involvement.

Glycogen storage diseases: New perspectives

Glycogen storage diseases （GSD） are inherited metabolic disorders of glycogen metabolism. Different hormones, including insulin, glucagon, and cortisol regulate the relationship of glycolysis, gluconeogenesis and glycogen synthesis. The overall GSD incidence is estimated 1 case per 20000-43000 live births. There are over 12 types and they are classified based on the enzyme deficiency and the affected tissue. Disorders of glycogen degradation may affect primarily the liver, the muscle, or both. Type I a involves the liver, kidney and intestine （and I b also leukocytes）, and the clinical manifestations are hepatomegaly, failure to thrive, hypoglycemia, hyperlactatemia, hyperuricemia and hyperlipidemia. Type Ilia involves both the liver and muscle, and lib solely the liver. The liver symptoms generally improve with age. Type IV usually presents in the first year of life, with hepatomegaly and growth retardation. The disease in general is progressive to cirrhosis. Type Ⅵ and Ⅳ are a heterogeneous group of diseases caused by a deficiency of the liver phosphorylase and phosphorylase kinase system. There is no hyperuricemia or hyperlactatemia. Type Ⅺ is characterized by hepatic glycogenosis and renal Fanconi syndrome. Type Ⅱ is a prototype of inborn lysosomal storage diseases and involves many organs but primarily the muscle. Types V and Ⅶ involve only the muscle.

Molecular profiles and long-term outcomes of Thai children with hepatic glycogen storage disease in Thailand

BACKGROUND Thus far,genetic analysis of patients clinically diagnosed with glycogen storage diseases(GSDs)in Thailand has not been reported.AIM To evaluate the clinical and biochemical profiles,molecular analysis and long-term outcomes of Thai children diagnosed with hepatic GSD.METHODS Children aged<18 years diagnosed with hepatic GSD and followed up at King Chulalongkorn Memorial Hospital were recruited.Whole-exome sequencing(WES)was performed to identify the causative gene variants.Medical records were assessed.RESULTS All eight children with histopathologically confirmed diagnosis were classified by WES into subtypes Ia(n=1),III(n=3),VI(n=3),and IX(n=1).A total number of 10 variants were identified including G6PC(n=1),AGL(n=4),PYGL(n=5),and PHKA2(n=1).AGL had two novel variants.The clinical manifestations were hepatomegaly(n=8),doll-like facies(n=3),wasting(n=2),and stunting(n=5).All patients showed hypoglycemia,transaminitis,and dyslipidemia.The mainstay of treatment was cornstarch supplementation and high-protein and low-lactosefructose diet.After a median follow-up time of 9.59 years,height turned to normal for age in 3/5 patients and none had malnutrition.Liver enzymes,blood sugar,and lipid profiles improved in all.CONCLUSION Hepatomegaly,transaminitis,and hypoglycemia are the hallmarks of GSD confirmed by liver histopathology.Molecular analysis can confirm the diagnosis or classify the subtype that might benefit from personalized treatment,prognosis,and long-term care.

Role of lipids in the control of autophagy and primary cilium signaling in neurons

The brain is,after the adipose tissue,the organ with the greatest amount of lipids and diversity in their composition in the human body.In neurons,lipids are involved in signaling pathways controlling autophagy,a lysosome-dependent catabolic process essential for the maintenance of neuronal homeostasis and the function of the primary cilium,a cellular antenna that acts as a communication hub that transfers extracellular signals into intracellular responses required for neurogenesis and brain development.A crosstalk between primary cilia and autophagy has been established;however,its role in the control of neuronal activity and homeostasis is barely known.In this review,we briefly discuss the current knowledge regarding the role of autophagy and the primary cilium in neurons.Then we review the recent literature about specific lipid subclasses in the regulation of autophagy,in the control of primary cilium structure and its dependent cellular signaling in physiological and pathological conditions,specifically focusing on neurons,an area of research that could have major implications in neurodevelopment,energy homeostasis,and neurodegeneration.

Dose-response effect of pre-exercise carbohydrates under muscle glycogen unavailability:Insights from McArdle disease

Background:This study aimed to determine the effect of different carbohydrate(CHO)doses on exercise capacity in patients with McArdle disease—the paradigm of“exercise intolerance”,characterized by complete muscle glycogen unavailability—and to determine whether higher exogenous glucose levels affect metabolic responses at the McArdle muscle cell(in vitro)level.Methods:Patients with McArdle disease(n=8)and healthy controls(n=9)underwent a 12-min submaximal cycling constant-load bout followed by a maximal ramp test 15 min after ingesting a non-caloric placebo.In a randomized,double-blinded,cross-over design,patients repeated the tests after consuming either 75 g or 150 g of CHO(glucose:fructose=2:1).Cardiorespiratory,biochemical,perceptual,and electromyographic(EMG)variables were assessed.Additionally,glucose uptake and lactate appearance were studied in vitro in wild-type and McArdle mouse myotubes cultured with increasing glucose concentrations(0.35,1.00,4.50,and 10.00 g/L).Results:Compared with controls,patients showed the“classical”second-wind phenomenon(after prior disproportionate tachycardia,myalgia,and excess electromyographic activity during submaximal exercise,all p<0.05)and an impaired endurance exercise capacity(-51%ventilatory threshold and55%peak power output,both p<0.001).Regardless of the CHO dose(p<0.05 for both doses compared with the placebo),CHO intake increased blood glucose and lactate levels,decreased fat oxidation rates,and attenuated the second wind in the patients.However,only the higher dose increased ventilatory threshold(+27%,p=0.010)and peak power output(+18%,p=0.007).In vitro analyses revealed no differences in lactate levels across glucose concentrations in wild-type myotubes,whereas a doseresponse effect was observed in McArdle myotubes.Conclusion:CHO intake exerts beneficial effects on exercise capacity in McArdle disease,a condition associated with total muscle glycogen unavailability.Some of these benefits are dose dependent.

Pediatric metabolic liver diseases:Evolving role of liver transplantation

Metabolic liver diseases(MLD)are the second most common indication for liver transplantation(LT)in children.This is based on the fact that the majority of enzymes involved in various metabolic pathways are present within the liver and LT can cure or at least control the disease manifestation.LT is also performed in metabolic disorders for end-stage liver disease,its sequelae including hepatocellular cancer.It is also performed for preventing metabolic crisis’,arresting progression of neurological dysfunction with a potential to reverse symptoms in some cases and for preventing damage to end organs like kidneys as in the case of primary hyperoxalosis and methyl malonic acidemia.Pathological findings in explant liver with patients with metabolic disease include unremarkable liver to steatosis,cholestasis,inflammation,variable amount of fibrosis,and cirrhosis.The outcome of LT in metabolic disorders is excellent except for patients with mitochondrial disorders where significant extrahepatic involvement leads to poor outcomes and hence considered a contraindication for LT.A major advantage of LT is that in the post-operative period most patients can discontinue the special formula which they were having prior to the transplant and this increases their well-being and improves growth parameters.Auxiliary partial orthotopic LT has been described for patients with noncirrhotic MLD where a segmental graft is implanted in an orthotopic position after partial resection of the native liver.The retained native liver can be the potential target for future gene therapy when it becomes a clinical reality.

Combined liver-kidney transplantation for rare diseases

Combined liver and kidney transplantation(CLKT)is indicated in patients with failure of both organs,or for the treatment of end-stage chronic kidney disease(ESKD)caused by a genetic defect in the liver.The aim of the present review is to provide the most up-to-date overview of the rare conditions as indications for CLKT.They are major indications for CLKT in children.However,in some of them(e.g.,atypical hemolytic uremic syndrome or primary hyperoxaluria),CLKT may be required in adults as well.Primary hyperoxaluria is divided into three types,of which type 1 and 2 lead to ESKD.CLKT has been proven effective in renal function replacement,at the same time preventing recurrence of the disease.Nephronophthisis is associated with liver fibrosis in 5%of cases and these patients are candidates for CLKT.In alpha 1-antitrypsin deficiency,hereditary C3 deficiency,lecithin cholesterol acyltransferase deficiency and glycogen storage diseases,glomerular or tubulointerstitial disease can lead to chronic kidney disease.Liver transplantation as a part of CLKT corrects underlying genetic and consequent metabolic abnormality.In atypical hemolytic uremic syndrome caused by mutations in the genes for factor H,successful CLKT has been reported in a small number of patients.However,for this indication,CLKT has been largely replaced by eculizumab,an anti-C5 antibody.CLKT has been well established to provide immune protection of the transplanted kidney against donor-specific antibodies against class I HLA,facilitating transplantation in a highly sensitized recipient.

Reduced-size liver transplantation for glycogen storage disease

BACKGROUND: Glycogen storage disease (GSD) is an inherited metabolic disorder in which the concentration and/or structure of glycogen in tissues is abnormal. Essentially, abnormalities in all known enzymes involved in the synthesis or degradation of glycogen and glucose have been found to cause some type of GSD. Liver and muscle have abundant quantities of glycogen and are the most common and seriously affected tissues. This study was to assess reduced-size liver transplantation for the treatment of GSD. METHODS: The clinical data from one case of GSD type I with hepatic adenoma was retrospectively analyzed. The clinical manifestations were hepatomegaly, delayed puberty, growth retardation, sexual immaturity, hypoglycemia, and lactic acidosis, which made the young female patient eligible for reduced-size liver transplantation. RESULTS: The patient recovered uneventfully with satisfactory outcome, including 12 cm growth in height and 5 kg increase in weight during 16 months after successful reduced-size liver transplantation. She has been living a normal life for 4 years so far. CONCLUSIONS: Reduced-size liver transplantation is an effective treatment for GSD with hepatomegaly and hepatic adenoma. Delayed puberty, growth retardation, hypoglycemia and lactic acidosis can be cured by surgery.

Double filtration plasmapheresis for pregnancy with hyperlipidemia in glycogen storage disease type Ia:A case report

BACKGROUND Glycogen storage disease type Ia(GSDIa) is an autosomal recessive inborn error of carbohydrate metabolism that is caused by deficiency of the enzyme glucose-6-phosphatase(G6Pase),leading to disturbed glycogenolysis and gluconeogenesis.Patients with GSDIa show severe fasting hypoglycemia,hyperlipidemia,hyperlactacidemia,and hyperuricemia,which are associated with fatal outcomes in pregnant women and fetuses.CASE SUMMARY Herein,we report the case of a 24-year-old female who on her first visit to the hospital,presented with pregnancy combined with extremely high hyperlipidemia and hyperlactic acidosis with anemia,and frequent hypoglycemia occurred during the treatment.Genetic tests revealed a mutation in the G6Pase gene(G6PC) at 17q21,the patient was finally diagnosed with glycogen storage disease type Ia for the first time after 22 years of inaccurate treatment.She has been treated with a continuous double filtration plasmapheresis(DFPP) strategy to remove blood lipids,and a cornstarch diet therapy.The patient did not develop pancreatitis during the course of the disease and a healthy baby girl weighing 3 kg was delivered.CONCLUSION Patients with GSDIa may be misdiagnosed as epilepsy.DFPP can be used to control hyperlipidemia in GSDIa patients during pregnancy.

Rare complication of inflammatory bowel disease-like colitis from glycogen storage disease type 1b and its surgical management:A case report

BACKGROUND Glycogen storage disease(GSD)is an autosomal recessive inborn metabolic disorder.Patients with GSD are prone to hypoglycaemia,hyperlactacidemia and bleeding.GSD type 1b(GSD-1b)patients specifically can develop neutropenia,recurrent bacterial infection and inflammatory bowel disease(IBD).Documentation of the long-term outcomes of surgical management of GSD-1b has been scarce,especially for Asian patients.We herein describe a case of GSD-1b complicated by IBD-like colitis and coloduodenal fistula.The patient was managed successfully with surgical intervention.CASE SUMMARY A 20-year-old Chinese lady confirmed by genetic testing to have GSD-1b was initially managed with uncooked cornstarch and granulocyte-colony stimulating factor.With recurrent abdominal symptoms,her condition was treated as clinical“Crohn’s disease”with mesalazine,prednisolone and azathioprine conservatively.Colonoscopy showed a tight stricture at the hepatic flexure.Subsequent computerized tomographic colonography revealed a phlegmon at the ileocaecal region with a suspected coloduodenal fistula.Eventually an exploratory laparotomy was performed and severe colitis at the ascending colon with coloduodenal fistula was confirmed.Right hemicolectomy with primary anastomosis and repair of the duodenum were performed.Surgical management of complications from GSD-1b associated IBD-like colitis has rarely been described.First-line treatment would usually be conservative.Surgical intervention like hemicolectomy is mainly reserved for refractory cases.CONCLUSION Surgical management of coloduodenal fistula in GSD-1b patients is a feasible and safe option when failed conservative management.

Minimally invasive surgery for glycogen storage disease combined with inflammatory bowel disease:A case report

BACKGROUND Inflammatory bowel disease(IBD)is rare in patients with glycogen storage disease(GSD).In GSD patients,a decrease in the number of neutrophils leads to prolonged intestinal infection,leading to the formation of chronic inflammation and eventually the development of IBD.Minimally invasive surgery for patients with IBD has been proven to reduce inflammatory responses and postoperative risks and ultimately promote rapid recovery.Herein we discuss minimally invasive surgery and the perioperative management in a patient with GSD and IBD.CASE SUMMARY A 23-year-old male had GSD Ib associated with IBD-like disease for 10 years.Despite standard treatments,such as mesalazine,prednisone and adalimumab,the patient eventually developed colonic stenosis with incomplete ileus.After adequate assessment,the patient was treated with minimally invasive surgery and discharged in stable condition.CONCLUSION Minimally invasive surgery for patients with IBD and GSD is safe,feasible and effective.

Cholesteryl ester storage disease of clinical and genetic characterisation: A case report and review of literature

BACKGROUND Cholesteryl ester storage disease(CESD)is a rare genetic disease.Its symptoms and severity are highly variable.CESD is a systemic disease that can lead to the accumulation of fat and inflammation in the liver,as well as gastrointestinal and cardiovascular disease.The majority of patients require liver transplantation due to decompensated cirrhosis.Enzyme replacement therapy has been approved based on a randomized trial.Our study aims to clinically and genetically evaluate two siblings with CESD who underwent liver transplantation,as well as their first-degree family members.CASE SUMMARY The siblings were compound heterozygous for the missense variant in LIPA exon 8,c.894G>A,(p.Gln298Gln)and a single base pair deletion,c.482del(p.Asn161Ilefs*19).Analyses of single nucleotide polymorphisms showed variants with an increased risk of fatty liver disease and fibrosis for both patients.Clinically,both patients show signs of recurrence of CESD in the liver after transplantation and additional gastrointestinal and cardiovascular signs of CESD.Three family members who were LIPA heterozygous had a lysosomal acid lipase activity below the reference value.One of these carriers,a seven-year-old boy,was found to have severe dyslipidemia and was subsequently treated with statins.CONCLUSION Our study underlines that CESD is a multi-organ disease,the progression of which may occur post-liver transplantation.Our findings underline the need for monitoring of complications and assessment of possible further treatment.

“Bull’s eye”appearance of hepatocellular adenomas in patients with glycogen storage disease type I-atypical magnetic resonance imaging findings:Two case reports

BACKGROUND Hepatocellular adenomas are rare tumors that can occur in patients with glycogen storage disease type I.CASE SUMMARY We herein report two cases of histologically proven hepatocellular adenomas in patients with glycogen storage disease type I.Magnetic resonance imaging(MRI)was performed after bolus injection of gadoxetate disodium,a liver-specific gadolinium-based MRI contrast agent.In the present cases,some of the hepatocellular adenomas showed unexpectedly a“bull’s eye”appearance on T2-weighted and post-contrast images,which was not previously described as imaging findings of hepatocellular adenomas in glycogen storage disease.A bull’s eye appearance on T2-weighted images can be encountered in both benign(i.e.,abscess)or malignant(i.e.,epithelioid hemangioendothelioma,cholangiocarcinoma,and metastases)hepatic lesions.CONCLUSION We present two cases of hepatocellular adenomas in patients with glycogen storage disease type 1,in which gadoxetate disodium-MRI showed atypical imaging findings for hepatocellular adenomas.At present there is no systematic study evaluating MRI findings of hepatocellular adenomas in patients with glycogen storage disease,further studies are needed to specifically investigate this issue.

Successful treatment of multiple hepatocellular adenomas with percutaneous radiofrequency ablation

Hepatocellular adenoma (HCA) is one of the important complications of glycogen storage disease type?Ia (GSD-Ia) because it can be transformed into hepatocellular carcinoma. Although surgical resection is a standard treatment of choice for solitary HCA, multiple HCAs in GSD-Ia patients present as therapeutic challenges for curative treatment. Therefore, treatment strategy according to malignant potential is important in management of HCAs in GSD-Ia. The authors present a case of histologically proven multiple HCAs without β-catenin mutations occurred in a GSD-Ia patient treated successfully with percutaneous radiofrequency ablation as a minimally invasive therapy.

Infliximab treatment of glycogenosis Ib with Crohn's-like enterocolitis: A case report

BACKGROUND Glycogen storage disease type Ib(GSD-Ib)is a glycogen metabolism disorder that leads to the manifestations of inflammatory bowel disease(IBD),especially Crohn’s disease(CD)-like colitis.Although biological agents are effective for treating CD,their application in the treatment of GSD-Ib with CD-like colitis has been rarely reported.CASE SUMMARY A 13-year-old Han male was diagnosed with GSD-Ib with CD.The patient was treated with granulocyte colony-stimulating factor.When he had symptoms of CD-like colitis,he was continuously pumped with enteral nutrition and administered oral mesalazine for 2 wk;however,the symptoms did not improve significantly.Hence,infliximab(IFX)was administered.Hitherto,the patient has been followed up for 1 year,and no clinical manifestations have been observed.After 6 mo of treatment(fifth IFX treatment),the disease activity index and all inflammatory indexes decreased,and a review of the colonoscopy data showed that the ulcers appeared smooth.CONCLUSION In this study,the patient was successfully treated with IFX.In cases of GSD-Ib,IBD should be highly considered.

Novel LIPA mutations in Mexican siblings with lysosomal acid lipase deficiency

Lysosomal acid lipase(LAL) deficiency is an underrecognized lysosomal disease caused by deficient enzymatic activity of LAL.In this report we describe two affected female Mexican siblings with early hepatic complications.At two months of age,the first sibling presented with alternating episodes of diarrhea and constipation,and later with hepatomegaly,elevated transaminases,high levels of total and low-density lipoprotein cholesterol,and low levels of highdensity lipoprotein.Portal hypertension and grade 2 esophageal varices were detected at four years of age.The second sibling presented with hepatomegaly,elevated transaminases and mildly elevated lowdensity lipoprotein and low high-density lipoprotein at six months of age.LAL activity was deficient in both patients.Sequencing of LIPA revealed two previously unreported heterozygous mutations in exon 4:c.253C>A and c.294C>G.These cases highlight the clinical continuum between the so-called Wolman disease and cholesteryl ester storage disease,and underscore that LAL deficiency represents a single disease with a degree of clinical heterogeneity.

Novelα-galactosidase A gene mutation in a Chinese Fabry disease family:A case report

BACKGROUND Fabry disease(FD)is a rare X-linked lysosomal storage disease caused by a deficiency of the enzymeα-galactosidase A.CASE SUMMARY Herein,we analyzed a four-generation Chinese family.The proband is a 57-yearold woman who was diagnosed with left ventricular hypertrophy and atrial fibrillation 7 years ago.Echocardiography showed an end-diastolic diameter of the interventricular septum of 19.9 mm,left ventricular end-diastolic diameter of 63.1 mm,and moderate-to-severe mitral regurgitation.Cardiac magnetic resonance indicated an enlarged left heart and right atrium,decreased left ventricular systolic and diastolic function,a left ventricular ejection fraction of 20%,and thickening of the left ventricular septum.In March 2019,gene and enzyme activity tests confirmed the diagnosis of FD.Her son was diagnosed with FD after gene and enzyme activity assay,and was prescribed agalsidase-βfor enzyme replacement therapy in July 2020.Two sisters of the proband were also diagnosed with FD by genetic testing.Both of them had a history of atrial fibrillation.CONCLUSION A novel mutation was identified in a Chinese family with FD,in which the male patient had a low level of enzyme activity,early-onset,and severe organ involvement.Comprehensive analysis of clinical phenotype genetic testing and enzyme activity testing helped in the diagnosis and treatment of this FD family.

Clinical and Technological Dependence Characteristics on a Series of Brazilian Cases with Infantile Onset Pompe Disease in Enzyme Replacement Therapy

Pompe disease (PD) is a rare inborn error of metabolism due to an abnormal acid alpha-glucosidase (GAA) activity that comprises glycogen breakdown mainly in the lysosomes. Since the introduction of enzyme replacement therapy (ERT), with recombinant human GAA for the early onset PD patient, a relevant field of clinical research due to the benefits regarding survival rate has been widely documented worldwide. Objective: To describe the clinical characteristics and the ERT effects in a series of Brazilian patients with infantile onset PD (IOPD) under ERT. Methods: Brazilian patients diagnosed with IOPD under ERT were recruited through their physicians participating in the International Pompe Disease Registry from 2009 to 2017. Data were collected by an online survey. Results: 10 IOPD patients were identified through the survey with a death rate of 30% and technology dependency rate reported as 80% (motor, respiratory or nutritional fields) of the patients. After the third year of ERT, motor disabilities were lost in 50% of ambulated patients. The overall characteristics were similar to international studies. Conclusion: Despite ERT benefits in cardiac involvement, motor disabilities seem to be much more compromised in IOPD patients, with high technology dependence, especially after three years of age.

Patella Alta and Trochlea Dysplasia Is Associated with Abnormal Type Ⅱ Collagen and Matrix Accumulation in Chondrocytes

The purpose of this study was to perform morphological and molecular analyses of articular cartilage from a 14-year-old boy with unusual cartilage lesions, patella alta and trochlea dysplasia in both knee joints and clinically examine two family members (sister, mother), also affected in their knee joints. Biopsies from the boy’s patella were used for: histological examination, Transmission Electron Microscopy (TEM) and DNA sequencing of the COL2A1 gene including Multiplex Ligation-dependent Probe Amplification (MLPA), for detection of DNA deletions and duplications. Clinical and radiological examination showed patella alta and trochlea dysplasia for the brother (type D), sister (type A) and mother (type A) with Insall-Salvati ratios of 1.50, 1.46 and 1.3. Light Microscopy (LM) of biopsies from the patient showed rhomboid chondrocytes in lacuna with deposition of protein aggregates in the ECM. TEM revealed abnormal type II collagen fibrils in aggregates and chondrocytes with abnormal matrix accumulation in rough Endoplasmic Reticulum (rER). Immunostaining showed that type II collagen was deposited intracellularly and in protein aggregates, together with type I collagen, indicating alterations in chondrocyte function and turnover of these molecules. DNA sequencing of 54 exons including extended DNA analysis with MLPA was non-conclusive. Conclusions: We suggest that patella alta and trochlea dysplasia for this patient is associated with collagen accumulation in chondrocytes, abnormal type II collagen heterofibrils in the ECM, cell death and cartilage with subnormal strength and increased risk of premature patellofemoral arthritis. A family with these disorders suggests that phenotype might be transmitted as an autosomal dominant trait.

Recent development and gene therapy for glycogen storage disease type Ia

Glycogen storage disease type Ia(GSD-Ia)is an autosomal recessive metabolic disorder caused by a deficiency in glucose-6-phosphatase-α(G6Pase-αor G6PC)that is expressed primarily in the liver,kidney,and intestine.G6Pase-αcatalyzes the hydrolysis of glucose-6-phosphate(G6P)to glucose and phosphate in the terminal step of gluconeogenesis and glycogenolysis,and is a key enzyme for endogenous glucose production.The active site of G6Pase-αis inside the endoplasmic reticulum(ER)lumen.For catalysis,the substrate G6P must be translocated from the cytoplasm into the ER lumen by a G6P transporter(G6PT).The functional coupling of G6Pase-αand G6PT maintains interprandial glucose homeostasis.Dietary therapies for GSD-Ia are available,but cannot prevent the long-term complication of hepatocellular adenoma that may undergo malignant transformation to hepatocellular carcinoma.Animal models of GSD-Ia are now available and are being exploited to both delineate the disease more precisely and develop new treatment approaches,including gene therapy.