Challenges in Gaucher disease: Perspectives from an expert panel

Area of Science:

• Medical Genetics
• Rare Diseases
• Metabolic Disorders

Background:

• Gaucher disease (GD) is a lysosomal storage disorder with varied clinical presentations.
• Understanding the distinct types of GD and their associated manifestations is crucial for effective management.
• Current research addresses key clinical and research areas including genetic sequencing, complications, and therapeutic approaches.

Purpose of the Study:

• To review and synthesize current knowledge on eight critical topics in Gaucher disease.
• To provide clinicians and researchers with an updated perspective on GD classification, manifestations, and management.
• To identify gaps in knowledge and areas for future research, particularly concerning neuronopathic GD and CNS-targeted therapies.

Main Methods:

• Focused literature review of eight key topics relevant to Gaucher disease.
• Synthesis of evidence regarding GD classification, neurological involvement, genetic testing, and associated conditions.
• Analysis of current treatment strategies, including enzyme replacement therapy (ERT) and substrate synthesis inhibition therapy (SSIT), and their efficacy.

Main Results:

• Gaucher disease is best classified into distinct types (1, 2, and 3) rather than a spectrum, with types 2 and 3 exhibiting progressive neuronopathic disease.
• Whole GBA1 sequencing is recommended over exome sequencing for comprehensive variant detection.
• Elevated risks of monoclonal gammopathy of undetermined significance (MGUS) and certain lymphomas are noted in GD patients.
• Pulmonary and bone complications are common, requiring advanced imaging like quantitative MRI for monitoring.
• Gaucheromas are benign neoplasms requiring further study for management.
• ERT and eliglustat are suitable first-line treatments for adults, with treatment switching being generally safe.
• A critical unmet need remains for treatments targeting the central nervous system (CNS) in neuronopathic GD and for Parkinson's disease risk reduction.

Conclusions:

• Distinct GD types necessitate tailored clinical approaches.
• Comprehensive genetic analysis and advanced monitoring are essential for managing GD complications.
• While current therapies are effective for systemic manifestations, CNS-targeted treatments are urgently needed for neuronopathic GD and potentially for Parkinson's disease risk in GBA1 variant carriers.