Objective: To describe patients with Type 1 Gaucher disease who developed a rare neurodegenerative disease other than synucleinopathies.

Background: Lysosomal dysfunction as a contributor to pathological mechanisms of neurodegeneration became apparent when mutations in GBA1, encoding the enzyme glucocerebrosidase, were identified as the most common genetic risk factor for developing synucleinopathies. Biallelic GBA1 mutations cause Gaucher disease. Mutations in GBA1 are identified at higher frequency in patients with parkinsonism, including atypical forms, such as Dementia with Lewy bodies. However, rare patients with Gaucher disease and other proteinopathies associated with neurodegeneration have been described. The mechanism of how glucocerebrosidase deficiency contributes to the pathogenesis in these proteinopathies, although not fully understood, highlights how lysosomal integrity is important for proper neuronal function.

Method: Patients were evaluated at the NHGRI Gaucher Disease Genetics Clinic at the National Institute of Health. We describe three unrelated individuals with type 1 Gaucher disease who presented with concurrent clinical neurodegenerative signs and symptoms seen in proteinopathies other than alpha-synuclein aggregation.

Results: Motor neuron disease, Rapid-onset Dystonia Parkinsonism, and Progressive Supranuclear Palsy respectively were identified in three different adult patients with Gaucher disease.

Conclusion: While an association between glucocerebrosidase deficiency with TDP-43 proteinopathy, mutations in ATP1A3, and tauopathies has not been widely reported, the development of these disorders in rare patients with Gaucher disease may provide additional clues regarding how lysosomal dysfunction contributes to neuronal instability. Clinicians caring for patients with Gaucher disease should expand monitoring of neurological status to include evidence of neurodegenerative disorders other than parkinsonism.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rare-neurodegenerative-phenotypes-in-patients-carrying-homozygous-gba1-mutations/