The Expanding Natural History of Type 3 Gaucher Disease in the Post Enzyme Replacement Era
Biochemical/Metabolic and Therapeutics
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Primary Categories:
- General Education
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Secondary Categories:
- General Education
Introduction:
Gaucher Disease is an autosomal recessive lysosomal storage disorder, caused by variants in GBA1 gene resulting in deficiency in the enzyme glucocerebrosidase, and accumulation glucocerebroside in various tissues. 3 phenotypes have been described: non-neuronopathic (Type 1), acute neuronopathic (Type 2), and chronic neuronopathic (Type 3).
Three decades after the approval of the first FDA-approved enzyme replacement therapy for Gaucher disease, two additional enzyme replacement therapies and two substrate reduction therapies have since been approved. These have shown to improve the visceral and hematological manifestations, however none of the available therapies cross the brain blood barrier, and the neurologic symptoms from the neuronopathic forms are untreated.
The objective is to gain a better understanding of the natural history of Type 3 Gaucher Disease, unveiled through therapeutic interventions that have modified the disease course and prolonged longevity.
Methods:
Retrospective analysis of clinical data describing patients with Gaucher disease seen at the National Institutes of Health, that have been treated with enzyme replacement therapy, substrate reduction therapy or other therapies, with last visit or contact in the past 20 years .
Results:
We describe a cohort of 30 patients with type 3 Gaucher disease. The most common genotype was L444P/L444P, median age at last evaluation 27.5 (4-72 years of age) and 16 were female (53.3%). The median age at symptom onset ranged from birth to early childhood (0 months – 5 years) and the most common presenting symptoms were organomegaly, developmental delay, anemia, bleeding and bone crises. 23% of patients had undergone splenectomy. Only one patient had seizures as presenting symptom.
In 93% of the neurological manifestations were evident between age 12 months to teenage years. The most common neurological findings were developmental delay, cognitive delay, ocular abnormalities (slow saccades), seizures, myoclonus, and psychiatric manifestations. 23% of patients had hearing loss, predominantly sensorineural. The cohort included one patient in her sixth decade of life with Parkinson disease.
Conclusion:
Therapeutic options currently available for Type 3 Gaucher disease improved visceral and hematological manifestations, thereby extending life expectancy and alleviating many symptoms. However, neurological manifestations remain untreated due to the inability of existing therapies to cross the blood-brain barrier. This highlights the urgent need for further research into targeted therapies that can effectively penetrate the brain. While in the past type 3 Gaucher disease GD been described as life-limiting, in the modern era longevity has greatly improved due to available treatments. As these individuals are living longer, the spectrum and heterogeneity of clinical features is becoming increasingly apparent.
Gaucher Disease is an autosomal recessive lysosomal storage disorder, caused by variants in GBA1 gene resulting in deficiency in the enzyme glucocerebrosidase, and accumulation glucocerebroside in various tissues. 3 phenotypes have been described: non-neuronopathic (Type 1), acute neuronopathic (Type 2), and chronic neuronopathic (Type 3).
Three decades after the approval of the first FDA-approved enzyme replacement therapy for Gaucher disease, two additional enzyme replacement therapies and two substrate reduction therapies have since been approved. These have shown to improve the visceral and hematological manifestations, however none of the available therapies cross the brain blood barrier, and the neurologic symptoms from the neuronopathic forms are untreated.
The objective is to gain a better understanding of the natural history of Type 3 Gaucher Disease, unveiled through therapeutic interventions that have modified the disease course and prolonged longevity.
Methods:
Retrospective analysis of clinical data describing patients with Gaucher disease seen at the National Institutes of Health, that have been treated with enzyme replacement therapy, substrate reduction therapy or other therapies, with last visit or contact in the past 20 years .
Results:
We describe a cohort of 30 patients with type 3 Gaucher disease. The most common genotype was L444P/L444P, median age at last evaluation 27.5 (4-72 years of age) and 16 were female (53.3%). The median age at symptom onset ranged from birth to early childhood (0 months – 5 years) and the most common presenting symptoms were organomegaly, developmental delay, anemia, bleeding and bone crises. 23% of patients had undergone splenectomy. Only one patient had seizures as presenting symptom.
In 93% of the neurological manifestations were evident between age 12 months to teenage years. The most common neurological findings were developmental delay, cognitive delay, ocular abnormalities (slow saccades), seizures, myoclonus, and psychiatric manifestations. 23% of patients had hearing loss, predominantly sensorineural. The cohort included one patient in her sixth decade of life with Parkinson disease.
Conclusion:
Therapeutic options currently available for Type 3 Gaucher disease improved visceral and hematological manifestations, thereby extending life expectancy and alleviating many symptoms. However, neurological manifestations remain untreated due to the inability of existing therapies to cross the blood-brain barrier. This highlights the urgent need for further research into targeted therapies that can effectively penetrate the brain. While in the past type 3 Gaucher disease GD been described as life-limiting, in the modern era longevity has greatly improved due to available treatments. As these individuals are living longer, the spectrum and heterogeneity of clinical features is becoming increasingly apparent.