ENOrphanet Journal of Rare Diseases | Clinical and Genetic Analyses of 17 Chinese Patients with GSD IXc Reveal CHIT as a Novel Biomarker for Treatment Monitoring
Date: January 30, 2026
Classification: Frontiers
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This study systematically analyzed the clinical, biochemical, genetic characteristics, and treatment responses of 17 Chinese patients with glycogen storage disease type IXc (GSD IXc), and for the first time proposed that Chitotriosidase (CHIT) could serve as a potential biomarker for monitoring treatment response. It also revealed the correlation between genotype and phenotype, providing new insights into disease management.
Literature Overview
The article 'Clinical and genetic analyses of 17 Chinese patients with glycogen storage disease type IXc', published in the journal Orphanet Journal of Rare Diseases, reviews and summarizes clinical manifestations, biochemical markers, gene mutation profiles, treatment responses, and follow-up data from 17 Chinese patients with glycogen storage disease type IXc (GSD IXc). The study found that abdominal distension, hypoglycemia, muscle weakness, and short stature were the main clinical features. All pediatric patients exhibited significantly elevated transaminases, and untreated adult patients had developed cirrhosis. Long-term follow-up confirmed that uncooked cornstarch (UCCS) therapy significantly improved blood glucose control, liver function, and growth parameters. Moreover, this study is the first to systematically evaluate the dynamic changes of Chitotriosidase (CHIT) in GSD IXc, observing a significant decline in CHIT levels with treatment, suggesting its potential as a biomarker for monitoring therapeutic response. Genetic analysis revealed 18 variants in the PHKG2 gene, 12 of which were novel, and patients with non-truncating variants showed better response to UCCS therapy, indicating a genotype-phenotype correlation. This study expands the clinical and genetic spectrum of GSD IXc, providing critical evidence for disease diagnosis, prognosis assessment, and personalized treatment.Background Knowledge
Glycogen storage disease type IXc (GSD IXc) is a rare autosomal recessive disorder caused by mutations in the PHKG2 gene, leading to functional deficiency of the gamma subunit of hepatic phosphorylase kinase (PhK), which disrupts glycogen breakdown and results in abnormal glycogen accumulation in hepatocytes. It is the most severe subtype among GSD IX, characterized clinically by hepatomegaly, hypoglycemia, growth retardation, elevated liver enzymes, and hyperlipidemia. Some patients may progress to liver fibrosis, cirrhosis, or even hepatocellular carcinoma. Due to overlapping phenotypes with other hepatic GSDs, definitive diagnosis relies on genetic testing. The PHKG2 gene, located at 16p11.2, encodes the catalytic gamma subunit of PhK. Its loss of function leads to reduced PhK activity and failure to effectively activate glycogen phosphorylase. Current treatment primarily involves UCCS to maintain stable blood glucose, supplemented by a high-protein diet, but lacks effective biomarkers for assessing treatment efficacy and prognosis. Chitotriosidase (CHIT), a marker of inflammation secreted by activated macrophages, is elevated in various lysosomal storage disorders. Recent studies suggest elevated CHIT levels in GSD types I, II, and IV, potentially reflecting chronic intrahepatic inflammation due to activation of Kupffer cells by glycogen or lipid accumulation. However, the pattern and clinical significance of CHIT changes in GSD IXc remain unclear. Additionally, although PHKG2 mutations have been reported, systematic genotype-phenotype correlations are still lacking. This study fills these knowledge gaps, providing new evidence for understanding the mechanisms and clinical management of GSD IXc.
Methods and Experiments
The study included 17 genetically confirmed GSD IXc patients (16 children and 1 adult), with retrospective analysis of clinical, biochemical, genetic, and treatment follow-up data. Clinical data included symptoms, signs, and growth parameters; biochemical markers covered fasting glucose, liver enzymes, lipids, lactate, uric acid, creatine kinase, and CHIT activity. CHIT testing excluded patients homozygous for the 24-bp duplication in the CHIT1 gene to avoid false-low readings. All pediatric patients received UCCS therapy (1.5–2.5 g/kg/day in four doses), and some underwent liver biopsy or transplantation. Genetic analysis used Sanger or whole-exome sequencing, with PHKG2 variants classified using ACMG guidelines and validated by Sanger sequencing. The splice variant c.96-11G>A was validated via cDNA sequencing to assess its impact on mRNA splicing. Five missense variants were evaluated through in vitro expression and Western blot analysis for protein expression. Statistical analysis was performed using GraphPad Prism to compare pre- and post-treatment metrics and differences across genotype groups.Key Findings and Insights
Implications and Future Directions
This study represents the largest clinical and genetic analysis of Chinese GSD IXc patients to date, significantly expanding the variant and phenotypic spectrum of the disease. It confirms that UCCS therapy effectively improves metabolic disturbances, liver function, and growth in GSD IXc patients, underscoring the importance of early diagnosis and intervention. Notably, the dynamic changes in CHIT levels offer a potential non-invasive tool for clinical monitoring of disease activity and treatment response, whose predictive value requires validation in larger cohorts.
The discovery of genotype–phenotype correlations suggests that PHKG2 variant types may guide personalized treatment strategies: patients with non-truncating variants may respond well to UCCS monotherapy, while those with truncating variants may require more aggressive interventions, such as earlier consideration of liver transplantation. Furthermore, the high frequency of the E157K variant suggests a potential mutation hotspot in Chinese and East Asian populations, which could be prioritized in genetic screening. Future studies should expand sample sizes and extend follow-up periods to assess long-term complication risks and explore the predictive role of CHIT in liver fibrosis progression.
Conclusion
This study systematically characterizes the clinical, biochemical, and genetic features of 17 Chinese patients with GSD IXc, confirming a more severe phenotype compared to other GSD IX subtypes, with pediatric patients commonly exhibiting hepatomegaly, hypoglycemia, muscle weakness, and growth retardation, along with significantly elevated liver enzymes. Long-term UCCS therapy significantly improves glucose control, liver function, and growth parameters, enabling catch-up growth. The study is the first to reveal a dynamic decline in Chitotriosidase (CHIT) levels during treatment, paralleling improvements in liver injury markers, highlighting its potential as a novel biomarker for monitoring GSD IXc therapy. Genetic analysis identified 18 PHKG2 variants, 12 of them novel, with c.469G>A being a recurrent hotspot, especially enriched in East Asian populations, suggesting a founder effect. Functional studies confirmed that c.96-11G>A causes aberrant splicing and that the R279C variant leads to reduced protein expression. Most importantly, patients carrying non-truncating variants showed superior response to UCCS therapy, with significantly lower post-treatment ALT/AST levels than those with truncating variants, revealing a clear genotype–phenotype correlation that informs personalized treatment strategies. In summary, this study not only expands the clinical and genetic spectrum of GSD IXc but also provides new biomarker and genotype-guided insights for disease management, emphasizing the importance of early diagnosis, long-term follow-up, and precision therapy.
