Orphanet Journal of Rare Diseases | Clinical and Genetic Landscape of Neuronal Gaucher Disease in Ukraine: Hepatosplenomegaly and Diagnostic Delay

Recommend:

This study elucidates the complex association between the GBA1 genotype and the phenotype of neuronal Gaucher disease, providing critical data support for early clinical identification and functional prediction of genetic variants.

 

Overview

This article, "Clinical and genetic landscape of neuronopathic gaucher disease in Ukraine: hepatosplenomegaly and diagnostic delay," published in the Orphanet Journal of Rare Diseases, systematically explores the clinical characteristics, genetic background, and status of diagnostic delays in types 2 and 3 neuronal Gaucher disease within a Ukrainian cohort, with particular emphasis on the importance of hepatosplenomegaly as an early warning signal.

Background Knowledge

Gaucher disease is a rare lysosomal storage disorder caused by the deficiency of β-glucocerebrosidase activity due to mutations in the GBA1 gene. This study aims to address a major pain point in the clinical diagnosis of neuronal Gaucher disease: severe diagnostic delays caused by the lack of specific early neurological symptoms. Currently, there remains a significant bottleneck in predicting the severity of the phenotype based on the GBA1 genotype, particularly for patients carrying variant combinations (R/O type) predicted to have residual enzyme activity, whose clinical manifestations are often more severe than expected. The focus of this study is to re-evaluate the value of hepatosplenomegaly in the early diagnosis of neuronal Gaucher disease through a large-sample retrospective analysis and to deeply analyze the actual impact of the GBA1 mutation spectrum on disease progression.

 

Pathogenicity: Assess the pathogenic potential of GBA1 gene variants, providing key reference for analyzing the function of rare disease variants

Learn More

 

Research Methods and Core Experiments

The authors conducted a retrospective cohort study on 92 patients with Gaucher disease diagnosed at the National Children's Specialized Hospital in Ukraine between 2001 and 2024, including 4 cases of type 2 and 6 cases of type 3. The study utilized leukocyte β-glucocerebrosidase activity assays combined with molecular analysis of the GBA1 gene (Sanger sequencing and NGS) for confirmation. Through detailed collection of clinical history, imaging examinations (ultrasound), and laboratory data, the study systematically evaluated the degree of hepatosplenomegaly, hematological abnormalities, and neurological involvement in patients.

Key Conclusions and Perspectives

• Type 2 Gaucher disease presents with onset in infancy, with an average onset age of 2.8 months and a short diagnostic delay (average 4.3 months). All patients exhibited severe hepatosplenomegaly and rapidly progressive neurological degeneration, with death occurring before 14 months of age.
• Type 3 Gaucher disease has a later onset (average 2.3 years) but an extremely long diagnostic delay (average 11.5 years). Ophthalmoplegia is the most common initial symptom (83%), and all patients presented with hepatosplenomegaly and hematological abnormalities upon diagnosis.
• Genotype analysis shows that even patients carrying GBA1 variant combinations predicted to have residual enzyme activity (such as R/O type) exhibit severe clinical courses, indicating that relying solely on residual enzyme activity prediction cannot accurately assess disease severity.
• Hepatosplenomegaly is a common systemic feature in the progression of neuronal Gaucher disease and should not be viewed as an isolated grading marker. When combined with early neurological symptoms (such as ophthalmoplegia or developmental regression), neuronal Gaucher disease should be highly suspected.

Research Significance and Outlook

This finding has profound implications for drug development and clinical monitoring. The study points out that while Enzyme Replacement Therapy (ERT) can effectively improve systemic symptoms such as hepatosplenomegaly, it cannot cross the blood-brain barrier to prevent neurological deterioration. Therefore, early identification of subtle neurological changes accompanying hepatosplenomegaly is crucial, as it directly relates to the accuracy of disease modeling and the timing of treatment, helping to reduce irreversible neurological damage.

 

Sequence Alignment: Rapidly align GBA1 gene sequences to precisely identify mutation sites causing neuronal Gaucher disease

Learn More

 

Conclusion

This study systematically描绘 (depicts) the clinical and genetic panorama of neuronal Gaucher disease in Ukraine for the first time, revealing distinct clinical trajectories between types 2 and 3. The core finding is that hepatosplenomegaly is often an early signal preceding neurological symptoms but is easily misdiagnosed or overlooked, leading to diagnostic delays of up to a decade. In-depth analysis of GBA1 gene mutations indicates that traditional genotype-phenotype correlation predictions have limitations, and residual enzyme activity cannot fully explain disease severity. This discovery emphasizes that in clinical practice, children with unexplained hepatosplenomegaly must undergo comprehensive evaluation combining neurological examinations to initiate Enzyme Replacement Therapy or supportive treatment as early as possible. Translating from laboratory to clinic, this study provides a solid empirical foundation for optimizing rare disease diagnostic pathways, enhancing specialist awareness, and improving national registry systems, playing a cornerstone role in improving the long-term prognosis of Gaucher disease patients.

 

Nataliia Samonenko, Nataliia Olkhovych, Olena Okhotnikova, and Nataliia Gorovenko. Clinical and genetic landscape of neuronopathic gaucher disease in Ukraine: hepatosplenomegaly and diagnostic delay. Orphanet Journal of Rare Diseases.