Glycogen Storage Disease Type Research Articles

Pompe Disease Complicated with Appendicular Torsion: A Rare Concurrence.

Pompe disease, also known as Glycogen Storage Disease Type II, is a rare disorder of glucose metabolism caused by congenital acid alpha-glucosidase (GAA) deficiency. A large amount of glycogen accumulates in the lysosomes, causing these to swell and rupture. Its incidence is about 1 in 40,000 to 1 in 50,000 newborns. The main features are hypotonia and cardiomyopathy. Only a few clinical cases of Pompe disease have been reported, and appendicular torsion has rarely been observed. Herein, we report a case of Pompe disease combined with appendicular torsion, both of which were diagnosed on autopsy pathology. The clinical diagnosis of this disease is difficult in developing countries, and it is mostly misdiagnosed as other types of heart disease. Once the clinical symptoms worsen, most of them die within a short period. Therefore, screening for neonatal genetic metabolic diseases for early diagnosis and treatment should be carried out. Key Words: Glycogen storage disease type II, Metabolic disease, Enzyme replacement therapy, Neonatal screening.

PCR269 People and Families Affected by Gsdia: An Analysis of Narrative Accounts Written by Caregivers and Individuals Living With GSDIa

Glycogen Storage Disease Type Ia (GSDIa) is a rare, inherited disorder that can lead to renal and hepatic complications, brain damage, and death. Dietary management based on frequent cornstarch consumption can cause gastrointestinal and nutritional issues, sleep disruption, and psychosocial problems. This study was designed to describe the individual experiences of those affected by GSDIa through qualitative methods by asking patients and caregivers to provide written summaries of how the condition affects them.

Favorable outcome of empagliflozin treatment in two pediatric glycogen storage disease type 1b patients.

Glycogen storage disease type 1b (GSD1b) is an ultra-rare autosomal recessive disorder, caused by mutations in SLC37A4 gene. Affected patients present with episodes of fasting hypoglycemia and lactic acidosis, hepatomegaly, growth retardation, hyperlipidemia and renal impairment. In addition, patients present neutropenia, neutrophil dysfunction and oral, and skin infections as well as a significant predisposition to develop inflammatory bowel disease (IBD). Low neutrophil counts and function is related to the toxic accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P). Recently, several reports have shown that off-label treatment with empagliflozin (EMPA), an inhibitor of the renal glucose transporter SGLT2, decreased blood 1,5-anhydroglucitol (1,5-AG), and neutrophil 1,5-AG6P, thus resulting in a new therapeutic option for neutropenia and neutrophil dysfunction in patients. Off-label treatment with EMPA was established in two GSD1b patients after signed informed consent. The patients were followed clinically. We monitored neutrophil counts and function, 1,5-AG levels in plasma and its renal clearance before and during EMPA treatment. A 17 year-old girl who had long standing oral ulcers and developed IBD, requiring systemic steroid and regular granulocyte colony-stimulating factor (GCSF) therapy and an 8 year-old boy who had steady non healing oral lesions were treated with empagliflozin during 18-24 months. Treatment led to increase of neutrophil counts and function with substantial clinical improvement. This included remission of IBD in the first patient which allowed to discontinue both GCSF and steroid therapy and resolution of oral lesions in both patients. The concentration of 1,5-AG in blood was greatly decreased within two weeks of treatment and remained stable thereafter. Repurposing of empagliflozin to treat neutropenia in two GSD1b patients was safe and resulted in the urinary excretion of 1,5-AG, the normalization of neutrophil function, and a remarkable improvement of neutropenia-related clinical traits. We showed for the first time that empagliflozin increases concomitantly the renal clearance of both 1,5-anhydroglucitol and glucose in GSD1b patients.

Empagliflozin Modifies Neutrophils' Subsets in Patients with Glycogen Storage Disease Type Ib By Increasing Mature Neutrophils and Decreasing Immature Neutrophils

Empagliflozin Modifies Neutrophils' Subsets in Patients with Glycogen Storage Disease Type Ib By Increasing Mature Neutrophils and Decreasing Immature Neutrophils

Oral SGLT2 Inhibitors in Glycogen Storage Disease Type Ib and G6PC3-Deficiency. Preliminary Results from an Off-Label Study of 21 Patients

Introduction Glycogen storage disease type Ib (GSDIb) and G6PC3-deficiency (G6PC3d) are two distinct genetic disorders associating neutropenia, bacterial infections susceptibility and inflamatory bowel disease (IBD), requiring GCSF therapy, and various immunotherapies. These neutropenias are caused either by a defect in the glucose-6-phosphate transporter of the ER or in the phosphatase G6PC3. These two defective proteins were recently shown to destroy a toxic metabolite, 1,5-anhydroglucitol-6-phosphate (1,5-AG6P), formed from the phosphorylation of a food derived polyol present in blood, 1,5-anhydroglucitol (1,5-AG), which otherwise accumulates in neutrophils, inhibits glycolysis and explains the neutropenia (Veiga-da-Cunha M, PMID: 30626647). As a direct result from this discovery, oral inhibitors of SGLT2 (iSGLT2s), the renal Na2+/glucose cotransporter 2 (e.g., empagliflozin or dapagliflozin) routinely used to treat type-2 diabetes were proposed to treat neutropenia in GSDIb and G6PC3d. Examples of such therapies have been successfully used in small cohorts of patients (Wortmann SB, PMID: 32294159; Boulanger, PMID: 35506446). We show preliminary results of the off-labelled study using iSGTL2s proposed to patients enrolled in the French severe chronic neutropenia registry (FSCNR). Methods: Patients (or their parents) with a genetic diagnosis of GSDIb or of G6PC3d enrolled in the FSCNR, signed an informed consent to participate to this observational study. Empaglifozin or mostly dapaglifozin were started at a dose of 0.4 mg/kg/day or 0.2 mg/kg/day respectively. The study was divided in 3 phases. During the pre-therapeutic period, information was collected on the medical history and various biological parameters (complete blood counts, 1,5-AG, concentration, bone marrow smears). The initiation period aims to adapt the iSGLT2 dose while GCSF and immunotherapy were tapered down. The maintenance therapy was an observational therapy period, during which iSGLT2 dose remained largely unchanged. Results Twenty-one patients (GSDIb n = 14; G6PC3d n =7) were enrolled and the median follow-up was 0.8 years. The median age at the start of therapy was 18.8 years [range 0.4 - 37.7 years]. Two are still in the initiation period, while 19 are in the maintenance therapy and their results are summarized in the table 1. During the initiation period, 6 patients continued taking the initial iSGTL2 dose, while a dosage increased appeared necessary in 13 others, both to lower GCSF dose and to optimally reduce 1,5-AG in plasma which was particularly high at onset. The only severe side-effect was related to neutrophilia observed in a patient with G6PC3d with transient digestive manifestations (recurrent vomits and stomach pains). Patients with GSDIb required a longer initiation period to achieve a clinical benefit. Three patients were not taking GCSF during the pre-therapeutic period. For the 16 patients treated with GCSF prior to iSGLT2 therapy (iSGTL2t), the mean dose of GCSF was 2.5 µg/kg/day; 9 of them stopped GCSF, 6 decreased their daily dose and 1 was unchanged. Overall, the mean dose of GCSF under iSGTL2t was reduced by 8-fold to 0.31 µg/kg/day. During the pre-therapeutic period 3 patients were treated for severe IBD which required anti-TNF therapy (and surgery for 2). Most remarkably all 3 patients stop IBD related treatments, without recurrence of symptoms, while on iSGTL2t. Comparing periods, we observed limited and non-statistically significative change among hematological parameters (table 1). Of note, stable values for neutrophils were found while the GCSF was either tapered down or withdrawn. Bone marrow inspection indicated a qualitatively change related to the aspect of the endoplasmic reticulum in neutrophils which appeared less damaged both seen on their morphology and on the electronic microscopy images. Maturation arrest was never observed and myeloid compartiment appears less overstimulated under iSGTL2t. Conclusion: iSGTL2s therapy in GSDIb and G6PC3d patients appeared to be a useful way to limit both GCSF therapy, infections and IBD manifestations. Initiation of iSGLT2s did not result in an instant effect. We often needed to adapt the dose of iSGTL2s both to spare GCSF therapy and to optimally lower 1,5-AG plasmatic level, indicating that its monitoring is useful to adapt the dosage. Further studies are required to define the best schedule of iSGTL2s in such subset of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Glycogen storage disease type Ia misdiagnosed as multiple acyl-coenzyme A dehydrogenase deficiency by mass spectrometry.

To report a case of glycogen storage disease (GSD) type Ia misdiagnosed as multiple acyl-coenzyme a dehydrogenase deficiency (MADD) by mass spectrometry. A 7 months old boy was admitted to our hospital for elevated transaminase levels lasting more than 1 month. His blood biochemistry showed hypoglycemia, metabolic acidosis, hyperlipidemia, elevated lactate and uric acid, elevated alanine amino transferase (ALT), aspartate amino transaminase (AST) and gamma-glutamyl transferase (GGT). Mass spectrometry analysis of blood and urine showed elevated blood acylcarnitines and dicarboxylic aciduria, indicating multiple acyl-coenzyme A dehydrogenase deficiency. Sanger sequencing of all exons of glucose-6-phosphatase (G6Pase) and electronic transfer flavoprotein dehydrogenase (ETFDH) was performed for the patient and his parents. Coding and flanking sequences of the G6Pase gene detected two heterozygous single base substitutions in the boy. One variant was in exon 1 (c.209G > A), Which was also detected in the father. Another was in exon 5 (c.648G > T), which was detected in the mother. Coding and flanking sequences of the ETFDH gene revealed no pathogenic/likely pathogenic variants in the boy. GSD Ia can manifest elevated blood acyl carnitines and dicarboxylic aciduria which were the typical clinical manifestations of MADD. So the patient with clinical manifestations similar to MADD is in need of differential diagnosis for GSD Ia. Genetic testing is helpful to confirming the diagnosis of inherited metabolic diseases.

Case report: Familial glycogen storage disease type IV caused by novel compound heterozygous mutations in a glycogen branching enzyme 1 gene

Glycogen storage disease type IV (GSD IV), caused by a mutation in the glycogen branching enzyme 1 (GBE1) gene, is a rare metabolic disorder with an autosomal recessive inheritance that involves the liver, neuromuscular, and cardiac systems. Here, we reported a case of familial GSD IV induced by novel compound heterozygous mutations in GBE1. The proband (at age 1) and her younger brother (at age 10months) manifested hepatosplenomegaly, liver dysfunction, and growth retardation at onset, followed by progressive disease deterioration to liver cirrhosis with liver failure. During the disease course, the proband presented rare intractable asymptomatic hypoglycemia. The liver pathology was in line with GSD IV. Both cases carried pathogenic compound heterozygous mutations in GBE1 mutations, i.e., a missense mutation (c.271T>A, p. W91R) in exon 2 and a deletion mutation in partial exons 3-7. Both mutations are first reported. The internationally pioneered split-liver transplantation was performed during progression to end-stage liver disease, and the patients had normal liver function and blood glucose after. This study broadens the mutation spectrum of the GBE1 gene and the phenotypic spectrum of GSD IV.

Yap signalling regulates ductular reactions in mice with CRISPR/Cas9-induced glycogen storage disease type Ia

ABSTRACT Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in the glucose-6-phosphatase (G6Pase, G6pc) enzyme, which catalyses the final step of gluconeogenesis and glycogenolysis. Accumulation of G6pc can lead to an increase in glycogen and development of fatty liver. Ductular reactions refer to the proliferation of cholangiocytes and hepatic progenitors, which worsen fatty liver progress. To date, however, ductular reactions in GSD-Ia remain poorly understood. Here, we studied the development and potential underlying mechanism of ductular reactions in GSD-Ia in mice. We first generated GSD-Ia mice using CRISPR/Cas9 to target the exon 3 region of the G6pc gene. The typical GSD-Ia phenotype in G6pc −/− mice was then analysed using biochemical and histological assays. Ductular reactions in G6pc −/− mice were tested based on the expression of cholangiocytic markers cytokeratin 19 (CK19) and epithelial cell adhesion molecule (EpCAM). Yes-associated protein 1 (Yap) signalling activity was measured using western blot (WB) analysis and quantitative real-time polymerase chain reaction (qRT-PCR). Verteporfin was administered to the G6pc −/− mice to inhibit Yap signalling. The CRISPR/Cas9 system efficiently generated G6pc −/− mice, which exhibited typical GSD-Ia characteristics, including retarded growth, hypoglycaemia, and fatty liver disease. In addition, CK19- and EpCAM-positive cells as well as Yap signalling activity were increased in the livers of G6pc −/− mice. However, verteporfin treatment ameliorated ductular reactions and decreased Yap signalling activity. This study not only improves our understanding of GSD-Ia pathophysiology, but also highlights the potential of novel therapeutic approaches for GSD-Ia such as drug targeting of ductular reactions.

ODP208 Hypoglycemia as a Presenting Feature of McArdle's Disease

Abstract Introduction McArdle's disease (glycogen storage disease type V) is an autosomal recessive disease caused by mutations in the gene encoding for the muscle isoform of glycogen phosphorylase (PYGM). Characteristic symptoms include exercise intolerance, myalgia, muscle stiffness. Approximately half develop rhabdomyolysis, myoglobinuria, and renal failure. Hypoglycemia is an uncommon presenting symptom. Case report A 36-year-old male, previous college football athlete presented with jitteriness and blurry vision while exercising over the last one year. Symptoms occur 12-15 minutes into aerobic exercise. Fingerstick blood sugar during these episodes were as low as 30 mg/dl and afterwards the patient reported fatigue all day long. Consuming high carbohydrate foods and fluids supplemented with dextrose prior to exercise mitigate his symptoms. He reported no fasting hypoglycemia. Retrospectively, the patient reports that for years he noticed feeling fatigued a few minutes into starting exerice which improves after short periods of rest "second wind phenomenon." He can perform heavy resistance exercise like weightlifting but struggles with sustained aerobic activity. Past medical history is significant for HLA B27 positivity, alopecia areata and uveitis. Medications include multivitamin and creatine supplements. Physical exam revealed a healthy, well developed muscular individual with no other remarkable findings. Family history is significant for McArdle's disease in his brother, diagnosed at age 20 based on a muscle biopsy after multiple episodes of rhabdomyolysis. Grandfather had diabetes mellitus and pancreatic carcinoma. Labs revealed a creatine kinase (CK) level of 1638.7 U/L (49-397 U/L), CK-MB 49.1 ((0.1-5.9 ng/ml), 8 AM morning cortisol of 12.3 ug/dl (4.2-22.4 ug/dl), A1c 5.3%. There was no myoglobinuria. Thyroid function tests were within normal limits. Investigations done during an episode of exercise induced hypoglycemia - fingerstick blood sugar 44 mg/dl, plasma blood glucose 56 mg/dl(65-99 mg/dl), Insulin <0.5 mU/L(3-25mU/l), C-Peptide 0.5ng/ml(1.1-4.4ng/ml), Proinsulin 1.1 pmol/L(0-10. 0 pmol/L). Insulin autoantibody was negative. This ruled out exercise induced hyperinsulinemia. IGF-1 and IGF-2 levels were normal. Genetic study performed by the Glycogen Storage Disease Panel showed PYGM c.2262del (p. Lys754Asnfs*49), Pathogenic, PYGM c.1537A>G (p. Ile513Val), Uncertain Significance, PYGM c.833G>C (p. Arg278Pro), Uncertain Significance. Subsequently, the patient's brother underwent genetic testing, which confirmed the presence of all three before-mentioned PYGM variants. His father was found to carry the two variants of undetermined significance, suggesting that the patient and his brother inherited the pathogenic variant from their deceased mother. Discussion The patient's medical history, along with his personal and family's genetic findings were found to be consistent with McArdle's disease. Our patient's presentation is unique in that his exercise tolerance is much higher as compared to most individuals with McArdle's and his presenting complaint was hypoglycemia. Additionally, one of the variants of uncertain significance is likely to be recognized as pathogenic in the future. Presentation: No date and time listed

Breath Analysis in Children with Ketogenic Glycogen Storage Diseases

(1) Background: The treatment goal of ketogenic glycogen storage diseases (GSDs) is appropriate control of hypoglycemia and other disturbances such as dyslipidemia. Monitoring and treatment of ketosis are known to improve outcomes. We used breath analysis to identify volatile organic compounds (VOCs) that correlate with serum ketones in order to provide a non-invasive method of monitoring ketosis. (2) Methods: Consecutive children with ketogenic GSDs were recruited from a single center during routine admission to monitor serum glucose and ketone levels. Five breath samples were collected from every patient at the same time of blood draws. SIFT-mass spectrometry was used to analyze breath samples. Univariate linear mixed-effects regression models for 22 known VOCs and either serum ketones or glucose were performed. (3) Results: Our cohort included 20 patients aged 5–15 years with a mean BMI of 20 kg/m2 (72% tile). Most patients had GSD type 0 (35%), while 25% had type IX. VOCs that showed a significant correlation with serum ketone levels included acetone (p < 0.0001), trimethylamine (p < 0.0001), pentane (p = 0.0001), 3-methylhexane (p = 0.0047), and carbon disulfide (p = 0.0499). No correlation was found between serum glucose and any VOC. (4) Conclusions: Breath analysis is a promising noninvasive tool that can be used to predict ketone serum levels in patients with GSD.

Dapagliflozin Prevents Kidney Glycogen Accumulation and Improves Renal Proximal Tubule Cell Functions in a Mouse Model of Glycogen Storage Disease Type 1b.

Mutations in SLC37A4, which encodes the intracellular glucose transporter G6PT, cause the rare glycogen storage disease type 1b (GSD1b). A long-term consequence of GSD1b is kidney failure, which requires KRT. The main protein markers of proximal tubule function, including NaPi2A, NHE3, SGLT2, GLUT2, and AQP1, are downregulated as part of the disease phenotype. We utilized an inducible mouse model of GSD1b, TM-G6PT-/-, to show that glycogen accumulation plays a crucial role in altering proximal tubule morphology and function. To limit glucose entry into proximal tubule cells and thus to prevent glycogen accumulation, we administered an SGLT2-inhibitor, dapagliflozin, to TM-G6PT-/- mice. In proximal tubule cells, G6PT suppression stimulates the upregulation and activity of hexokinase-I, which increases availability of the reabsorbed glucose for intracellular metabolism. Dapagliflozin prevented glycogen accumulation and improved kidney morphology by promoting a metabolic switch from glycogen synthesis toward lysis and by restoring expression levels of the main proximal tubule functional markers. We provide proof of concept for the efficacy of dapagliflozin in preserving kidney function in GSD1b mice. Our findings could represent the basis for repurposing this drug to treat patients with GSD1b.

VP.34 Two-year follow-up of muscle strength and function in patients with glycogen storage disease type IIIa

Glycogen storage disease type IIIa (GSDIIIa) is an autosomal recessive disorder caused by mutations in the AGL gene coding for the glycogen debranching enzyme. The symptoms start in childhood with liver involvement and progress at adulthood with skeletal muscle weakness. With imminent therapeutic trials, quantitative documentation of disease progression is essential. The objective of this study is to identify the most affected skeletal muscle measures over 2 years of follow-up. The 6-minutes walk test (6MWT), knee (Biodex torquemeter) and ankle (MyoAnkle dynamometer) flexion/extension torques, as well as muscle function measure (MFM) were performed at 2 years interval. Forty-one patients aged from 10 to 66 years old (28±15 y), 59% females, were included. At baseline, the 6-minute walk distance (6MWD), knee and ankle flexion/extension torques, expressed as a percentage of predicted value (%pred), as well as the 3 dimensions of the MFM (D1, D2, D3) and the MFM total score, were all significantly lower than the maximum score of 100% (P<0.01). This reflects significant impairment in walking, knee and ankle joints muscle strength, standing and transfers (MFM D1), axial and proximal (MFM D2) and distal (MFM D3) motricity. After 2-years of follow-up, only MFM D1 and the MFM total score were slightly but significantly reduced (paired Wilcoxon test, P=0.016 and P=0.010, respectively). Because the age of onset of MFM D1 degradation was previously established around 35 years (Decostre 2017), the paired Wilcoxon test was performed only for patients aged at least 34 years (n=15). In this small sample, MFM D3 and knee extension strength were significantly impaired (P<0.05), but not MFM D1 (probably because 2 patients improved their MFM D1 score). In conclusion, the MFM and the knee extension strength are the most promising outcome measures for this slowly progressive disease. A longer follow-up is ongoing.

Gene Therapy Hits Its Stride in the Clinic

Gene Therapy Hits Its Stride in the Clinic

Development of a clinically validated in vitro functional assay to assess pathogenicity of novel GAA variants in patients with Pompe disease identified via newborn screening.

Purpose: The addition of Pompe disease (Glycogen Storage Disease Type II) to the Recommended Uniform Screening Panel in the United States has led to an increase in the number of variants of uncertain significance (VUS) and novel variants identified in the GAA gene. This presents a diagnostic challenge, especially in the setting of late-onset Pompe disease when symptoms are rarely apparent at birth. There is an unmet need for validated functional studies to aid in classification of GAA variants. Methods: We developed an in vitro mammalian cell expression and functional analysis system based on guidelines established by the Clinical Genome Resource (ClinGen) Sequence Variant Interpretation Working Group for PS3/BS3. We validated the assay with 12 control variants and subsequently analyzed eight VUS or novel variants in GAA identified in patients with a positive newborn screen for Pompe disease without phenotypic evidence of infantile-onset disease. Results: The control variants were analyzed in our expression system and an activity range was established. The pathogenic controls had GAA activity between 0% and 11% of normal. The benign or likely benign controls had an activity range of 54%–100%. The pseudodeficiency variant had activity of 17%. These ranges were then applied to the variants selected for functional studies. Using the threshold of <11%, we were able to apply PS3_ supporting to classify two variants as likely pathogenic (c.316C > T and c.1103G > A) and provide further evidence to support the classification of likely pathogenic for two variants (c.1721T > C and c.1048G > A). One variant (c.1123C > T) was able to be reclassified based on other supporting evidence. We were unable to reclassify three variants (c.664G > A, c.2450A > G, and c.1378G > A) due to insufficient or conflicting evidence. Conclusion: We investigated eight GAA variants as proof of concept using our validated and reproducible in vitro expression and functional analysis system. While additional work is needed to further refine our system with additional controls and different variant types in order to apply the PS3/BS3 criteria at a higher level, this tool can be utilized for variant classification to meet the growing need for novel GAA variant classification in the era of newborn screening for Pompe disease.

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

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

Clinical characteristics and genetic analysis of a Chinese pedigree affected by glycogen storage disease type Ia with gout as the first manifestation

To explore the clinical and genetic characteristics of a Chinese pedigree affected by glycogen storage disease (GSD) type Ia with gout as the first manifestation. Clinical and biochemical data of the pedigree were collected. Available members of the pedigree were subjected to gene sequencing, and the result was analyzed by bioinformatics software. The pedigree was followed up for five years. The proband was a young female manifesting recurrent gout flare, hypoglycemia, and hypertriglyceridemia. One of her younger brothers also presented with dysplasia and hepatic adenoma. Gene sequencing revealed that the proband and her younger brother both harbored c.1022T>A (p.I1e341Asn) and c.230+5G>A compound heterozygous variants of the G6PC gene , which were inherited from their father and mother, respectively. Among these, the c.230+5G>A is an intron region variant which was unreported previously, and bioinformatics analysis showed that it may impact mRNA splicing of the gene. The proband was treated with raw corn starch, allopurinol, and fenofibrate. Gout was well controlled, and she had given birth to a baby girl without GSD. GSD Ia should be considered among young gout patients with hypoglycemia and hepatomegaly, for which gene sequencing is warranted. GSD Ia has a good prognosis after comprehensive treatment with diet and medicine.

243.1: Pediatric Liver Transplantation Indications and Outcomes in Glycogen Storage Disease: A Single Center Experience

Introduction: Glycogen storage diseases (GSDs) are inherited metabolic disorders result from impaired glycogen storage, glycogen or glucose breakdown. Liver transplantation (LT) is considered as a treatment option for patients with glycogen storage diseases present with hepatic malignancy, liver failure or metabolic decompensation. GSD type Ia is associated with mutations in the G6PC gene due to deficiency of glucose-6-phosphotase, while glycogen storage disease type 9 results from phosphorylase kinase deficiency, an enzyme necessary for glycogen breakdown. Herein, we present our experience and transplantation outcomes in 7 pediatric patients with GSD who underwent LT. Methods: We retrospectively analyzed data from patients diagnosed with GSD who underwent LT between 1993-2021 years. Results: LT was performed in 6 patients with GSD type 1a and one patient with GSD type 9. Four patients had a family history of consanguinity (3 patients 1st degree, 1 patient 2nd degree). Mean age of diagnosis was 7.28 (1-24) months. Mean age of LT was 128.5 (13-216) months. Transplantation indications were hepatic adenoma (4/7), poor metabolic control (4/7) and cirrhosis (1/7). Extra-hepatic findings included proteinuria (4/7), Focal segmental glomerulosclerosis (1/7), proximal tubulopathy (4/7), nephrolithiasis (2/7), hyperlipidemia (7/7), delayed puberty (3/7), hypertension (2/7), short stature (6/7), epilepsy (2/7) and osteoporosis (4/7). One patient with GSD1a underwent cataract surgery. Three patients with GSD1a incidentally had the same G6PC gene mutations (c.247C>T). Three patients had normal cognitive functions and development (WISC-R Test). Two patients had mild where one patient had moderate mental retardation. One patient had %30 developmental delay (AGTE Test). Six patients underwent LT from living-related donors while one patient had cadaveric donor. Patients who underwent LT from live donors received left lateral segment. Explant liver pathology revealed variable numbers (1-12) of hepatic adenoma in 4 patients. Hepatocellular carcinoma (HCC) was detected in one patient. Serum lactate, uric acid and triglyceride levels normalized after LT. Tubulopathy resolved in one patient while epilepsy continued in two patients. Height SD scores were improved in 4 patients while remained unchanged in one patient after 5-year follow up. Acute graft rejection was detected in 4 patients. Mean follow up time was 80 (3-183) months. All patients are still alive and routinely followed up at our department. Conclusion: LT improved the quality of life in our GSD patients with metabolic decompensation and severe disease manifestations. Biochemical parameters (lactate, uric acid and triglyceride levels) normalized after transplantation. Our patients displayed improved height growth. LT should be considered in GSD patients with poor metabolic control despite dietary management, hepatic malignancy or progressive liver failure.

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, β, 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.

Peripheral neuropathy caused by vitamin B12 deficiency in a patient with glycogen storage disease type Ⅰa

本文报道了1例糖原累积病Ⅰa型患者，病程中出现双下肢麻木无力、步态不稳、双足踩棉花感，检查提示周围神经病变，病因考虑维生素B12缺乏性周围神经病变，经过甲钴胺治疗后症状逐渐缓解。提示对于周围神经病变患者，应当将维生素B12缺乏作为鉴别诊断之一。糖原累积病Ⅰa型是一种罕见的常染色体隐性遗传性疾病，患者常采用以生玉米淀粉为基础的饮食治疗，应当合理膳食，注意保证维生素和微量元素的均衡摄入，积极预防维生素B12缺乏等情况的发生。.

P4.03: Anesthetic Management of a Glycogen Storage Disease Type 1A With Air Embolism During Liver Transplantation: A Case Report

P4.03: Anesthetic Management of a Glycogen Storage Disease Type 1A With Air Embolism During Liver Transplantation: A Case Report