Eye movement biomarkers allow for the definition of phenotypes in Gaucher Disease

Abstract

Background Neurological forms of Gaucher disease, the inherited disorder of β-Glucosylceramidase caused by bi-allelic variants in GBA1, is a progressive disorder which lacks a disease-modifying therapy. Systemic manifestations of disease are effectively treated with enzyme replacement therapy, however, molecules which cross the blood–brain barrier are still under investigation. Clinical trials of such therapeutics require robust, reproducible clinical endpoints to demonstrate efficacy and clear phenotypic definitions to identify suitable patients for inclusion in trials. The single consistent clinical feature in all patients with neuronopathic disease is the presence of a supranuclear saccadic gaze palsy, in the presence of Gaucher disease this finding serves as diagnostic of ‘type 3’ Gaucher disease. Methods We undertook a study to evaluate saccadic eye movements in Gaucher patients and to assess the role of the EyeSeeCam in measuring saccades. The EyeSeeCam is a video-oculography device which was used to run a protocol of saccade measures. We studied 39 patients with non-neurological Gaucher disease (type 1), 21 patients with type 3 (neurological) disease and a series of 35 healthy controls. Mean saccade parameters were compared across disease subgroups. Results We confirmed the saccadic abnormality in patients with type 3 Gaucher disease and identified an unexpected subgroup of patients with type 1 Gaucher disease who demonstrated significant saccade parameter abnormalities. These patients also showed subtle neurological findings and shared a GBA1 variant. Conclusions This striking novel finding of a potentially attenuated type 3 Gaucher phenotype associated with a specific GBA1 variant and detectable saccadic abnormality prompts review of current disease classification. Further, this finding highlights the broad spectrum of neuronopathic Gaucher phenotypes relevant when designing inclusion criteria for clinical trials.

The spectrum of neurological manifestations and genotype–phenotype correlation in Indian children with Gaucher disease

“…reflecting the slowly progressive nature of the disease (Benko et al, 2011). Further, it was shown that saccadic eye movements could be used as a biomarker for disease progression (Donald et al, 2020). In the present study, we could assess the eye movements in 32 of 45 GD patients in our cohort who had a median age of The most common allele in our study was c.1448T>C which was found in 76%, compared to the study by Sheth et al (2018) where it was found in 62% of Indian GD patients.…”

“…Objective measurement of this finding can serve as a tool for diagnosis of type 3 GD at an early age. There are several methods used to measure these saccadic eye movements like the scleral search coil method and computer-based trackers like Eye-SeeCam; these methods have variable success in detecting the condition (Donald et al, 2020).…”

“…Very few studies have looked into the oculomotor findings being used as biomarkers for the disease, specifically the neurological phenotype of GD (Donald et al, 2020; Tylki‐Szymańska et al, 2010). No studies in the Indian population have looked into the use of video‐oculography as a biomarker for the disease.…”

In-depth phenotyping for clinical stratification of Gaucher disease

“…Forty patients previously classified as type 1, non-neuronopathic Gaucher disease at enrolment, were examined opportunistically by a neurologist as a convenience sample. This supplementary examination included the assessment of saccadic eye movements as part of a parallel study and in all but one, a video-oculographic assessment was undertaken using EyeSeeCam [ 41 ]. Twenty-five patients were selected at random and 15 were examined because of clinical features of severe systemic disease and/or with GBA1 genotypes recognised to be adverse: L444P, R463C, W184R in homozygous or heterozygous form as well as rare alleles (including the RecNciI complex variant).…”

Metabolomic Study Using Time-of-Flight Mass Spectrometry Reveals Novel Urinary Biomarkers for Gaucher Disease Type 1

“…GD patients present a wide spectrum of clinical manifestations where three subtypes can be distinguished. GD type 1 is a more attenuated form of the disease and corresponds to approximately 95% of all GD cases. , Patients can, in some cases, experience mild neurological impairments in addition to bone, hematological, visceral, and occasionally pulmonary complications. GD type 2, which refers to acute neuronopathic GD, is the most severe form of the disease and is associated with an early onset and important neurological impairments .…”