To describe clinical and laboratory characteristics, emphasizing the evolution of patients with hepatic glycogen storage diseases (GSDs) followed in Brazilian reference centers. Multicenter, retrospective study involving 13 centers, using RedCap platform. 132 patients were included: 63 (47.8%) GSD type I (56 Ia, 7 Ib), 13 (9.8%) with type III (12 IIIa, 1 IIIb), 1 (0.8%) type IV, 6 (4.5%) type VI, and 49 (37.1%) with type IX (28 IXa, 7 IXb, and 14 IXc). Type I patients presented earlier (4 months) and had more episodes of hypoglycemia at clinical presentation (p < 0.001). Anthropometric data at admission revealed impaired growth, with a tendency toward short stature across the groups (median -2.06, -1.89, and -1.96 among type I, III, and IX respectively). The median body mass index (BMI) z-scores at admission for all three types were above +1. Only patients with type IX demonstrated significant improvement in height (p = 0.007) and BMI (p = 0.020) z-scores during follow-up. Regarding laboratory tests, significant decreases were observed in total cholesterol, triglycerides, venous lactate and aminotransferases in patients with types I and IX. Hepatic GSDs are heterogeneous diseases. There is a significant height impairment with a troublesome trend to overweight and obesity, especially in type I. Although there is improvement in aminotransferases, cholesterol, and triglycerides with follow-up, adherence to treatment remains a challenge.

Glycogen storage disease type IX (GSD IX) arises from hepatic phosphorylase b kinase (PhK) deficiency attributable to pathogenic variants in the PHKA2, PHKB, and PHKG2 genes. This multicenter retrospective study evaluated clinical and biochemical data from 52 patients diagnosed across three European countries, with a median follow-up of 9.3 years (range: 1-49). In the cohort, 86.5% were classified as GSD IXa, whereas GSD IXb and IXc accounted for 7.7% and 3.8%, respectively; one diagnosis was based solely on enzymatic testing. Null variants in PHKA2 consistently resulted in severe PhK deficiency, whereas missense variants and in-frame deletions were associated with variable enzymatic impairment (8/19 tested cases). The median age at symptom onset was 1.6 years, and the mean age at diagnosis was 2.0 years. Predominant manifestations included hepatomegaly (82%), elevated aminotransferases (81%), hypertriglyceridemia (71%), hypercholesterolemia (67%), hypoglycemia (46%), hyperlactatemia (38%), and short stature (30%). Aberrant apolipoprotein C-III glycosylation was detected in 80% of analyzed samples. Nutritional intervention was associated with improved growth (height SD score - 0.8 ± 1.3 vs -0.2 ± 1.65; p = 0.031) and fewer documented fasting hypoglycemia episodes (20/44 vs 9/44; p = 0.012), although hepatomegaly frequently persisted. Liver biopsies showed steatosis, fibrosis, and/or chronic hepatitis in 52% of examined cases. A single hepatic adenoma was identified in a 14-year-old male. Overall, the clinical course of GSD IX was favorable, with hepatomegaly, elevated liver enzymes, and dyslipidemia as the most prevalent features. Severe hypoglycemic episodes were uncommon, and no clear genotype-phenotype correlation emerged.

Glycogen storage disease type IXc (GSD IXc) is an ultra-rare disorder impairing liver glycogen degradation, caused by a defect in phosphorylase kinase (PhK) γ subunit in the liver encoded by PHKG2. We aim to investigate the clinical, biochemical, genetic, therapeutic, and follow-up characteristics of 17 GSD IXc patients. Medical records were retrieved, focusing on clinical (height, complications etc.), biochemical [blood glucose, liver transaminases, chitotriosidase (Chit), etc.], genetic, treatment, and follow-up data for 17 patients (8 males, 9 females) with GSD IXc including 16 pediatric patients and one adult. Abdominal distension (16/16), hypoglycemia (16/16), muscular weakness (12/16), and short stature (5/16) were among the most common presenting features in 16 pediatric patients. At first visit, all 16 pediatric patients showed increased alanine aminotransferase and aspartate aminotransferase. Elevated gamma-glutamyl transferase, triglyceride, lactate, uric acid and total cholesterol were found in 15/15, 10/14, 7/13, 7/14 and 2/14 pediatric patients, respectively. Creatine kinase levels were within normal range in 14/14 patients. The adult patient was diagnosed with liver cirrhosis on her first visit at 36 years. Five out of sixteen pediatric patients achieved hepatomegaly remission after 8.6 ± 4.0 years of uncooked cornstarch (UCCS). The standard deviation scores for ΔHeight in 16 pediatric patients increased from - 1.76 ± 1.16 to 0.05 ± 1.02 (p < 0.0001). Significant improvements were observed in preprandial blood glucose levels and liver transaminases (all p < 0.05). Elevated Chit levels at an early stage of therapy decreased with UCCS [44.47 (9.52, 70.03) to 8.22 (6.37, 18.89) nmol/ml/h, p = 0.02]. One girl received liver transplantation and her clinical manifestations were greatly improved. Eighteen PHKG2 variants were identified, including twelve novel variants and one recurrent variant [c.469G > A, p.E157K (allele frequency: 11/34, 32.4%)]. The c.96-11G > A variant was found to cause a 9 bp retention on the right-hand side of intron 1. Patients with biallelic nonnull variants showed better response to UCCS therapy compared to those with null variants. This study expanded the clinical and variant spectrums of GSD IXc. Chit might be used as a biomarker for monitoring the treatment. Differential response to UCCS therapy based on variant type suggest a genotype-phenotype correlation.

Glycogen storage disease (GSD) type IX γ2 is a rare inborn error of metabolism where a defect in glycogenolysis leads to the inability to break down glycogen in the liver. Patients with GSD IX γ2 develop hypoglycemia and advanced liver disease, placing them at risk for liver transplantation. This study evaluates the efficacy of liver-directed AAV gene therapy in a murine model of GSD IX γ2. Phkg2-/- mice underwent treatment with AAV gene therapy (AAV9-LSP-mPhkg2, 5 × 1012 vg/kg, intravenous delivery) at ages 3 or 6 months and were treated for either 2 weeks, 3 months, or 12 months. Results demonstrated that AAV gene therapy reduced GSD IX γ2 disease burden across all primary end points. AAV gene therapy also persisted across the mouse lifespan and reduced preexisting liver fibrosis. This work provides preclinical data supporting AAV gene therapy as a definitive treatment for GSD IX γ2.

Objective: To investigate the clinical manifestations, pathological features, and genetic variant characteristics of children with glycogen storage disease type Ⅸa (GSD Ⅸa). Methods: A retrospective case series analysis was conducted to collected and analyzed the medical history, biochemical markers, liver ultrasound results, liver histopathological findings, genotypes, treatment regimens, and follow-up data of 4 pediatric patients diagnosed with GSD IXa in the Department of Infectious Diseases at Xiamen Children's Hospital from January 2018 to May 2024. All patients were confirmed by genetic testing. Results: All 4 pediatric patients diagnosed with GSD Ⅸa were male. The ages of onset were 8 months, 2 years, 3 years and 3 months, 1 year and 5 months, respectively, with initial presentations including chronic diarrhea (Case 1), incidentally detected transaminase elevation during routine examinations (Cases 2 and 3), and delayed motor development (Case 4). Diagnosis was confirmed at ages 10 months, 3 years, 3 years 4 months and 1 year 6 months, respectively.At diagnosis, anthropometric parameters and biochemical profiles revealed:Height: 68 cm (<P3), 96 cm (P25-50), 94 cm (P3-10), and 94 cm (P3-10).Weight: 7 kg (<P3), 17 kg (P90-97), 14.4 kg (P25-50), and 10.5 kg (P25-50).Alanine aminotransferase: 299, 500, 271, and 313 U/L (reference range 0-40 U/L).Aspartate aminotransferase: 285, 543, 337 and 357 U/L (reference range 0-40 U/L).Fasting glucose: 2.80, 3.67, 2.98, and 3.66 mmol/L (reference range 3.90-6.10 mmol/L).Lactate: 4.3, 2.1, 1.3, and 2.6 mmol/L (reference range 0.5-2.2 mmol/L).Triglycerides: 5.22, 1.38, 1.32, and 1.88 mmol/L (reference range 0.56-1.70 mmol/L).Case 1 exhibited poor adherence to uncooked cornstarch therapy during initial treatment, with no significant improvement in biochemical parameters. Follow-up imaging at age 4 revealed hepatic adenoma. Subsequent improvement in therapeutic compliance led to biochemical normalization, reduced hepatic adenoma size, and growth parameters of 113 cm (P10-25) and 26 kg (P90-97) at 6 years 2 months. Cases 2-4 demonstrated biochemical improvement with regular uncooked cornstarch therapy and no evidence of hepatic adenoma.Liver histopathology in Cases 1-3 confirmed glycogen accumulation consistent with GSD, without cirrhotic changes. Genetic analysis identified PHKA2 variations in all cases: 2 missense variants, 1 frameshift variant and 1 nonsense variant. The c.2839dup and c.3267G>A variants represent novel pathogenic mutations. Conclusions: GSD Ⅸa in pediatric patients is predominantly characterized by hepatomegaly, hepatic dysfunction, and hypoglycemia. While uncooked cornstarch therapy typically yields favorable prognoses, a subset of patients may develop hepatic adenomas. Notably, children with hepatic adenoma exhibited younger age of onset, significant growth retardation, and more severe metabolic disturbances, suggesting that hepatic adenoma development may be closely linked to the severity of metabolic dysregulation. 目的： 探讨糖原贮积病（GSD）Ⅸa型患儿的临床表现、病理及基因变异特征。 方法： 回顾性病例总结，收集并分析2018年1月至2024年5月在厦门市儿童医院感染科经基因确诊的4例GSD Ⅸa型患儿的病史、生化指标、肝脏超声、肝组织病理结果、基因型、治疗及随访资料。 结果： 4例GSD Ⅸa型患儿均为男性，发病年龄分别为8月龄、2岁龄、3岁3月龄、1岁5月龄，以慢性腹泻（例1）、体检发现转氨酶升高（例2、3）、运动发育迟缓（例4）起病，确诊年龄分别为10月龄、3岁龄、3岁4月龄、1岁6月龄。确诊时身高68 cm（<P3）、96 cm（P25~50）、94 cm（P3~10）、94 cm（P3~10），体重7 kg（<P3）、17 kg（P90~97）、14.4 kg（P25~50）、10.5 kg（P25~50），丙氨酸氨转氨酶299、500、271、313 U/L（参考值0~40 U/L），天冬氨酸转氨酶285、543、337、357 U/L（参考值0~40 U/L），空腹血糖2.80、3.67、2.98、3.66 mmol/L（参考值3.90~6.10 mmol/L），乳酸4.3、2.1、1.3、2.6 mmol/L（参考值0.5~2.2 mmol/L），甘油三酯5.22、1.38、1.32、1.88 mmol/L（参考值0.56~1.70 mmol/L）。例1患儿初期生玉米淀粉治疗依从性差，生化指标无明显改善，4岁随访影像学发现肝腺瘤，随后治疗依从性提高，6岁2月龄随访身高113 cm（P10~25），体重26 kg（P90~97），生化指标好转，肝腺瘤缩小。3例（例2~4）患儿均未发现肝腺瘤，规律生玉米淀粉治疗后生化指标改善。3例（例1~3）患儿肝组织病理符合GSD病理表现，均无肝硬化。4例患儿中PHKA2基因错义变异2例、移码变异1例、无义变异1例，其中c.2839dup和c.3267G>A为新发现的致病性变异。 结论： GSD Ⅸa型患儿主要表现为肝大、肝功能异常和低血糖，生玉米淀粉治疗预后较好，但少数也可出现肝腺瘤。伴肝腺瘤患儿的发病年龄小、生长发育延迟明显、代谢紊乱程度重，提示肝腺瘤发生可能和代谢紊乱严重相关。. Glycogen storage diseases (GSDs) are inherited inborn errors of carbohydrate metabolism that result in abnormal glycogen storage. The onset can range from neonatal life to adulthood, and clinical manifestations result either from a failure to convert glycogen into energy or the toxic accumulation of glycogen.  Glycogen is a branched polymer comprised of glucose monomers (see Image. Glycogen, Free Glucose Release, and Glycogen Storage Diseases, Figure 1). After a meal, the plasma glucose level rises, stimulating the storage of the excess in cytoplasmic glycogen. The liver contains the highest percentage of glycogen by weight (about 10%), whereas muscles can store about 2% by weight. Nevertheless, since the total muscle mass is greater than the liver mass, the total mass of glycogen in muscles is about twice that of the liver. When needed, the glycogen polymer can be broken down into glucose monomers and utilized for energy production. Defects in the enzymes and transporters for these processes cause GSDs. An increasing number of GSDs are being identified, but most are very rare. These subtypes are classified numerically in the order of recognition and identification of the enzyme defect causing the disorder. Classification of Glycogen Storage Disorder GSDs that primarily affect the liver include the following: Glycogen synthase-2 deficiency (GSD type 0a). Glucose-6-phosphatase deficiency (GSD type Ia). Glucose-6-phosphate transporter deficiency (GSD type Ib) . Glycogen debrancher deficiency (GSD type III) . Glycogen branching enzyme deficiency (GSD type IV) . Liver phosphorylase deficiency (GSD type VI) . Phosphorylase kinase deficiency (GSD type IXa). GLUT2 deficiency or Fanconi-Bickel disease. GSDs that primarily affect the skeletal muscles include the following: Muscle phosphorylase deficiency (GSD type V). Phosphofructokinase deficiency (GSD type VII). Phosphoglycerate mutase deficiency (GSD type X). Lactate dehydrogenase A deficiency (GSD type XI) . Aldolase A deficiency (GSD type XII); β-enolase deficiency (GSD type XIII). Phosphoglucomutase-1 deficiency (GSD type XIV). GSDs that affect both skeletal and cardiac muscles include the following: Lysosomal acid maltase deficiency (GSD type IIa). Lysosome-associated membrane protein 2 deficiency (GSD type IIb). Glycogenin-1 deficiency (GSD type XV). Muscle glycogen synthase deficiency (GSD type 0b).