Clinical, Imaging, Genetic, and Disease Course Characteristics in Patients With GM2 Gangliosidosis: Beyond Age of Onset

Abstract

Background and objectives: GM2 gangliosidoses, a group of autosomal-recessive neurodegenerative lysosomal storage disorders, result from β-hexosaminidase (HEX) deficiency with GM2 ganglioside as its main substrate. Historically, GM2 gangliosidoses have been classified into infantile, juvenile, and late-onset forms. With disease-modifying treatment trials now on the horizon, a more fine-grained understanding of the disease course is needed.

Methods: We aimed to map and stratify the clinical course of GM2 gangliosidoses in a multicenter cohort of pediatric and adult patients. Patients were stratified according to age at onset and age at diagnosis. The 2 resulting GM2 disease clusters were characterized in-depth for respective disease features (detailed standardized clinical, laboratory, and MRI assessments) and disease evolution.

Results: In 21 patients with GM2 gangliosidosis (17 Tay-Sachs, 2 GM2 activator deficiency, 2 Sandhoff disease), 2 disease clusters were discriminated: an early-onset and early diagnosis cluster (type I; n = 8, including activator deficiency and Sandhoff disease) and a cluster with very variable onset and long interval until diagnosis (type II; n = 13 patients). In type I, rapid onset of developmental stagnation and regression, spasticity, and seizures dominated the clinical picture. Cherry red spot, startle reactions, and elevated AST were only seen in this cluster. In type II, problems with balance or gait, muscle weakness, dysarthria, and psychiatric symptoms were specific and frequent symptoms. Ocular signs were common, including supranuclear vertical gaze palsy in 30%. MRI involvement of basal ganglia and peritrigonal hyperintensity was seen only in type I, whereas predominant infratentorial atrophy (or normal MRI) was characteristic in type II. These types were, at least in part, associated with certain genetic variants.

Discussion: Age at onset alone seems not sufficient to adequately predict different disease courses in GM2 gangliosidosis, as required for upcoming trial planning. We propose an alternative classification based on age at disease onset and dynamics, predicted by clinical features and biomarkers, into type I-an early-onset, rapid progression cluster-and type II-a variable onset, slow progression cluster. Specific diagnostic workup, including GM2 gangliosidosis, should be performed in patients with combined ataxia plus lower motor neuron weakness to identify type II patients.

Figure 1. GM2 Clusters Based on Differences in Disease Progression

Tay-Sachs (patients 3, 5, 6, 8–21), activator deficiency (patients 4, 7), and Sandhoff disease (patients 1, 2) according to age at diagnosis (end point of the bar) and onset of first symptoms, as well as age at first MRI (magnetic resonance imaging) indicating 2 disease clusters (type I patients 1–8; type II patients 9–21).

Figure 2. β-Hexosaminidase A Activity in nmol/h/10⁶ Cells

GM2 disease cluster 1 included patients with Sandhoff disease (SD) and activator deficiency (AD). Minimal permissible value for β-hexosaminidase A assay was set as 6.48 nmol/h/10⁶ cells (dashed line).

Figure 3. MRI Findings (Multiple Answers Possible)

GM2 disease cluster 1 shown in dark blue [I], in total 8 patients. GM2 disease cluster 2 shown in light blue [II], in total 13 patients.

Figure 4. MRI Findings in GM2

MRI T2w sagittal (A) and coronal (B), in a patient with Tay-Sachs disease, aged 40 years, showing infratentorial atrophy with enlarged spaces between the foliae of the cerebellar hemispheres and the vermis (arrow). By contrast, supratentorial structures appear normal. MRI T2w in a patient (C) with Tay-Sachs disease at age 26 months and patient (D) also with Tay-Sachs disease at age 13 months showing peritrigonal signal hyperintensity (thick arrow) also affecting the optic radiation, basal ganglia appear mildly hyperintense and swollen, and the anterior capsula interna is difficult to distinguish (thin arrow). MRI T2w axial (E) and coronal (F), in a patient with Sandhoff disease, aged 24 months, showing hypomyelination. The entire cerebellar and cerebral white matter is hyperintense; signal hypointensity appears only in the corpus callosum (arrow) and as a stripe in the external capsule. Basal ganglia appear mildly hyperintense and swollen.

Figure 5. Schematic Illustration of Signs and Symptoms in GM2 Disease

Symptoms characteristic for type I in dark blue and for type II in light blue. MRI type I (involvement of the basal ganglia and peritrigonal signal hyperintensity); MRI type II (predominant infratentorial atrophy or normal MRI). AST = aspartate transaminase; LDH = lactate dehydrogenase.