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.

This case report describes a novel use of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors in a patient whose glycogen storage disease (GSD) was unmasked by statin therapy. Evidence-based guidelines for the management of hyperlipidemia in patients with concurrent neuromuscular disorders (NMD) remain limited. We report the case of a 46-year-old man with hyperlipidemia, treated with simvastatin, who presented with 2 days of thigh pain without weakness or dark urine. He was diagnosed with statin-associated muscle symptoms. On further interview, the patient recalled experiencing thigh muscle soreness decades earlier while in the military, at which time his creatine phosphokinase (CPK) ranged between 1,200 and 3,000 U/L. He admitted not disclosing this history or a prior muscle biopsy. Muscle biopsy and electromyography/nerve conduction velocity studies were followed by whole-exome sequencing, which demonstrated hemizygosity for c.2369+1 G>T, a pathogenic variant in the PHKA1 gene, consistent with GSD IXd. He was subsequently treated with 2 PCSK9 inhibitors (first evolocumab, then alirocumab). A comprehensive literature review identified only 2 previously reported cases of GSD treated with alirocumab. Even if not volunteered, a history of muscle symptoms should be actively sought before initiating statins, with baseline CPK measurement if indicated. As statins are increasingly prescribed, additional cases of GSD may be unmasked, underscoring the need to define optimal therapy for hyperlipidemia in NMD, including GSD. We propose a specific role for PCSK9 inhibitors in patients with statin intolerance and GSD IXd, which has not been previously reported.

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.