Rapid and long-lasting efficacy of high-dose ambroxol therapy for neuronopathic Gaucher disease: A case report and literature review

Abstract

Gaucher disease (GD) is a lysosomal storage disorder caused by a deficiency in the GBA1-encoded enzyme, β-glucocerebrosidase. Enzyme replacement therapy is ineffective for neuronopathic Gaucher disease (nGD). High-dose ambroxol has been administered as an alternative treatment for a group of patients with nGD. However, little is known about the clinical indication and the long-term outcome of patients after ambroxol therapy. We herein report a case of a female patient who presented with a progressive disease of GD type 2 from 11 months of age and had the pathogenic variants of p.L483P (formerly defined as p.L444P) and p.R502H (p.R463H) in GBA1. A combined treatment of imiglucerase with ambroxol started improving the patient's motor activity in 1 week, while it kept the long-lasting effect of preventing the deteriorating phenotype for 30 months. A literature review identified 40 patients with nGD, who had received high-dose ambroxol therapy. More than 65% of these patients favorably responded to the molecular chaperone therapy, irrespective of p.L483P homozygous, heterozygous or the other genotypes. These results highlight the long-lasting effect of ambroxol-based chaperone therapy for patients with an expanding spectrum of mutations in GBA1.

Keywords: Gaucher disease; ambroxol; chaperone; genotype; glucocerebrosidase; therapy.

FIGURE 1

Clinical profiles and the treatment course of the present case. (a) May‐Grunwald‐Giemsa staining for Gaucher cells (arrows) in the bone‐marrow smear. Scale, 10 μm. (b) Sagittal T1‐weighted (left) and axial fluid‐attenuated inversion recovery (FLAIR, middle) image on day 24 of admission. No parenchymal lesion was detected in the FLAIR image at 3 months after discharge (right). (c) Clinical course of the patient. Treatments are shown at the top. Neurological findings and laboratory data are depicted in the middle and lower schemes, respectively. ACE, angiotensin‐converting enzyme; TRACP‐5b, Tartrate‐Resistant Acid Phosphatase 5b.

FIGURE 2

A mutational landscape of 40 patients who received ambroxol therapy for neuronopathic Gaucher disease. (a) The gene structure of GBA1 located at chromosome 1q22. Shaded boxes represent the 11 protein‐coding exons spanning the 6.8‐kb region in the negative strand of the human genome. The left‐to‐right direction corresponds to that of transcription. Annotations indicate 23 pathogenic variants identified in patients with neuronopathic Gaucher disease. Horizontal bars represent the domain structure of GCase. Red: mutant alleles identified in the present patient. All the 40 patients having these variants were reported to receive the ambroxol treatment. (b) Pie chart indicates the number and frequency (%) of mutant alleles among 80 alleles identified in the 40 patients (panel a). —, unidentified variant. (c) A stereographic structure of GCase (UniProt: A0A068F658). The location of amino acid residues harboring nGD‐associated variants is schematically shown.