Comparative case series demonstrating disease modifying outcome with early ambroxol and enzyme replacement therapy in acute neuronopathic Gaucher disease

Gaucher disease (GD) is an autosomal recessive inborn error of metabolism caused by acid β-glucocerebrosidase deficiency, which presents with a wide spectrum of clinical manifestations, ranging from perinatal-lethal to asymptomatic forms. GD type 1 (GD1) is the most frequent visceral form, whereas types 2 (GD2) and 3 (GD3) are associated with neurodegeneration (neuronopathic GD, nGD) and share overlapping manifestations, presenting as a continuum of neurological disease severity. Traditionally, GD2 is the most severe form and has a rapidly progressive course with death by age two to four years. Currently available treatments for GD include enzyme replacement therapy and substrate reduction therapy to ameliorate visceral, hematologic, and skeletal abnormalities; however, they are not efficacious for neurological manifestations. More recently, ambroxol has been suggested as an augmentative pharmacological chaperone for nGD. This comparative case series of three patients aims to demonstrate the impact of early neonatal initiation of ambroxol on neurological outcomes in our index case (Patient A), compared to two other patients (Patients B and C) who began ambroxol treatment at 10 months and 4 years and 1 month of age, respectively, after a later diagnosis of nGD with already established neurological symptoms. Patient A has normal age-related developmental milestones at four years, while Patients B and C have persistence of developmental delay albeit some forward progression in the former. Our report highlights that early neonatal diagnosis and ambroxol therapy could potentially be a game changer in mitigating disease progression in nGD by modifying the natural history of GD2. Expanding newborn screening will facilitate early diagnosis and significantly impact clinical outcomes and quality of life in GD patients with early initiation of treatment.